CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity▿
Identifieur interne : 000B36 ( Pmc/Checkpoint ); précédent : 000B35; suivant : 000B37CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity▿
Auteurs : Makoto Yamashita [Japon] ; Takanori Tomozawa [Japon] ; Masayo Kakuta [Japon] ; Akane Tokumitsu [Japon] ; Hatsumi Nasu [Japon] ; Shuku Kubo [Japon]Source :
- Antimicrobial Agents and Chemotherapy [ 0066-4804 ] ; 2008.
Abstract
Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(
Url:
DOI: 10.1128/AAC.00333-08
PubMed: 18955520
PubMed Central: 2612152
Affiliations:
Links toward previous steps (curation, corpus...)
Links to Exploration step
PMC:2612152Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity<xref ref-type="fn" rid="fn2">▿</xref> </title><author><name sortKey="Yamashita, Makoto" sort="Yamashita, Makoto" uniqKey="Yamashita M" first="Makoto" last="Yamashita">Makoto Yamashita</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Tomozawa, Takanori" sort="Tomozawa, Takanori" uniqKey="Tomozawa T" first="Takanori" last="Tomozawa">Takanori Tomozawa</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Kakuta, Masayo" sort="Kakuta, Masayo" uniqKey="Kakuta M" first="Masayo" last="Kakuta">Masayo Kakuta</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Tokumitsu, Akane" sort="Tokumitsu, Akane" uniqKey="Tokumitsu A" first="Akane" last="Tokumitsu">Akane Tokumitsu</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Nasu, Hatsumi" sort="Nasu, Hatsumi" uniqKey="Nasu H" first="Hatsumi" last="Nasu">Hatsumi Nasu</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Kubo, Shuku" sort="Kubo, Shuku" uniqKey="Kubo S" first="Shuku" last="Kubo">Shuku Kubo</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18955520</idno><idno type="pmc">2612152</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612152</idno><idno type="RBID">PMC:2612152</idno><idno type="doi">10.1128/AAC.00333-08</idno><date when="2008">2008</date><idno type="wicri:Area/Pmc/Corpus">000261</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000261</idno><idno type="wicri:Area/Pmc/Curation">000261</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000261</idno><idno type="wicri:Area/Pmc/Checkpoint">000B36</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000B36</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity<xref ref-type="fn" rid="fn2">▿</xref> </title><author><name sortKey="Yamashita, Makoto" sort="Yamashita, Makoto" uniqKey="Yamashita M" first="Makoto" last="Yamashita">Makoto Yamashita</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Tomozawa, Takanori" sort="Tomozawa, Takanori" uniqKey="Tomozawa T" first="Takanori" last="Tomozawa">Takanori Tomozawa</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Kakuta, Masayo" sort="Kakuta, Masayo" uniqKey="Kakuta M" first="Masayo" last="Kakuta">Masayo Kakuta</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Tokumitsu, Akane" sort="Tokumitsu, Akane" uniqKey="Tokumitsu A" first="Akane" last="Tokumitsu">Akane Tokumitsu</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Nasu, Hatsumi" sort="Nasu, Hatsumi" uniqKey="Nasu H" first="Hatsumi" last="Nasu">Hatsumi Nasu</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author><author><name sortKey="Kubo, Shuku" sort="Kubo, Shuku" uniqKey="Kubo S" first="Shuku" last="Kubo">Shuku Kubo</name><affiliation wicri:level="1"><nlm:aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement><region type="région">Région de Kantō</region></placeName></affiliation></author></analytic><series><title level="j">Antimicrobial Agents and Chemotherapy</title><idno type="ISSN">0066-4804</idno><idno type="eISSN">1098-6596</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(<italic>O</italic>)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (<italic>P</italic> < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Antimicrob Agents Chemother</journal-id><journal-id journal-id-type="publisher-id">aac</journal-id><journal-title>Antimicrobial Agents and Chemotherapy</journal-title><issn pub-type="ppub">0066-4804</issn><issn pub-type="epub">1098-6596</issn><publisher><publisher-name>American Society for Microbiology (ASM)</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18955520</article-id><article-id pub-id-type="pmc">2612152</article-id><article-id pub-id-type="publisher-id">0333-08</article-id><article-id pub-id-type="doi">10.1128/AAC.00333-08</article-id><article-categories><subj-group subj-group-type="heading"><subject>Antiviral Agents</subject></subj-group></article-categories><title-group><article-title>CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity<xref ref-type="fn" rid="fn2">▿</xref> </article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yamashita</surname><given-names>Makoto</given-names></name><xref ref-type="aff" rid="aff0"></xref><xref ref-type="fn" rid="fn1">†</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Tomozawa</surname><given-names>Takanori</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Kakuta</surname><given-names>Masayo</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Tokumitsu</surname><given-names>Akane</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Nasu</surname><given-names>Hatsumi</given-names></name><xref ref-type="aff" rid="aff0"></xref></contrib><contrib contrib-type="author"><name><surname>Kubo</surname><given-names>Shuku</given-names></name><xref ref-type="aff" rid="aff0"></xref><xref ref-type="fn" rid="fn1">†</xref></contrib></contrib-group><aff id="aff0">Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan</aff><author-notes><fn id="cor1"><label>*</label><p>Corresponding author. Mailing address: Biological Research Laboratories IV, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa, Tokyo 140-8710, Japan. Phone: 81-3-3492-3131. Fax: 81-3-5436-8578. E-mail: <email>yamashita.makoto.yr@daiichisankyo.co.jp</email></p></fn><fn id="fn1"><label>†</label><p>M.Y. and S.K. contributed equally to this study.</p></fn></author-notes><pub-date pub-type="ppub"><month>1</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>27</day><month>10</month><year>2008</year></pub-date><volume>53</volume><issue>1</issue><fpage>186</fpage><lpage>192</lpage><history><date date-type="received"><day>11</day><month>3</month><year>2008</year></date><date date-type="rev-recd"><day>25</day><month>4</month><year>2008</year></date><date date-type="accepted"><day>10</day><month>10</month><year>2008</year></date></history><permissions><copyright-statement>Copyright © 2009, American Society for Microbiology</copyright-statement></permissions><self-uri xlink:title="pdf" xlink:href="zac00109000186.pdf"></self-uri><abstract><p>Two neuraminidase (NA) inhibitors, zanamivir (Relenza) and oseltamivir phosphate (Tamiflu), have been licensed for the treatment of and prophylaxis against influenza. In this paper, the new potent NA inhibitor R-125489 is reported for the first time. R-125489 inhibited the NA activities of various type A and B influenza viruses, including subtypes N1 to N9 and oseltamivir-resistant viruses. The survival effect of R-125489 was shown to be similar to that of zanamivir when administered intranasally in a mouse influenza virus A/Puerto Rico/8/34 infection model. Moreover, we found that the esterified form of R-125489 showed improved efficacy compared to R-125489 and zanamivir, depending on the acyl chain length, and that 3-(<italic>O</italic>)-octanoyl R-125489 (CS-8958) was the best compound in terms of its life-prolonging effect (<italic>P</italic> < 0.0001, compared to zanamivir) in the same infection model. A prolonged survival effect was observed after a single administration of CS-8958, even if it was given 7 days before infection. It is suggested that intranasally administered CS-8958 works as a long-acting NA inhibitor and shows in vivo efficacy as a result of a single intranasal administration.</p></abstract></article-meta></front><floats-wrap><fig position="float" id="f1"><label>FIG. 1.</label><caption><p>Chemical structures of R-125489 and CS-8958.</p></caption><graphic xlink:href="zac0010977900001"></graphic></fig><fig position="float" id="f2"><label>FIG. 2.</label><caption><p>In vivo efficacy of CS-8958 and R-125489 in a mouse influenza virus infection model. Influenza A virus A/PR/8/34-infected (500 PFU, 0 h) mice were given 0.2 μmol/kg of CS-8958 (filled squares), R-125489 (open squares), zanamivir (filled circles), and saline (open circles) at 4 h before infection and 4 h and 18 h p.i. The dose of 0.2 μmol/kg corresponded to 95, 69, and 66 μg/kg for CS-8958, R-125489, and zanamivir, respectively. The number of surviving mice was monitored for 20 days p.i. (<italic>n</italic> = 10). (Results were not significant for the R-125489 administration group versus the zanamivir administration group [<italic>P</italic> = 0.0732; log rank test]).</p></caption><graphic xlink:href="zac0010977900002"></graphic></fig><fig position="float" id="f3"><label>FIG. 3.</label><caption><p>In vivo efficacy of the prodrug of R-125489 with acyl chains of various lengths in a mouse influenza virus infection model. Influenza A virus A/PR/8/34-infected (1,500 PFU, 0 h) mice given 0.3 μmol/kg of R-125489-C<sub>8</sub> (CS-8958, filled squares), R-125489-C<sub>10</sub> (filled triangles), R-125489-C<sub>6</sub> (open triangles), R-125489-C<sub>4</sub> (open squares), zanamivir (filled circles), and saline (open circles) (a) or R-125489-C<sub>8</sub> (CS-8958, filled squares), R-125489-C<sub>10</sub> (filled triangles), R-125489-C<sub>14</sub> (open triangles), R-125489-C<sub>16</sub> (open squares), zanamivir (filled circles), and saline (open circles) (b) at 4 h before infection and 4 h and 17 h p.i. The number of surviving mice was monitored for 20 days p.i. (<italic>n</italic> = 10 to 12).</p></caption><graphic xlink:href="zac0010977900003"></graphic></fig><fig position="float" id="f4"><label>FIG. 4.</label><caption><p>In vivo efficacy of the prophylactic intranasal administration of CS-8958 or zanamivir in a mouse influenza virus infection model. An intranasal dose of 0.5 μmol/kg of CS-8958 (filled squares), zanamivir (filled circles), or saline (open circles) was intranasally administered once at 10, 7, 4, or 1 day before infection (−10d, −7d, −4d, and −1d), and mice were infected with influenza A (A/PR/8/34) virus at 500 PFU/mouse on day 0. The dose of 0.5 μmol/kg corresponded to 236 μg/kg for CS-8958 and 166 μg/kg for zanamivir. The number of surviving mice was monitored for 20 days p.i. (<italic>n</italic> = 10). (Results were significant for the group given zanamivir at −1 day versus the group given saline [<italic>P</italic> = 0.0151]. Results were not significant for the three other zanamivir administration groups versus the saline administration group. Results were significant for all CS-8958 groups [<italic>P</italic> values of 0.0230 for the group dosed at −10 days and <0.0001 for the other three groups; log rank test]).</p></caption><graphic xlink:href="zac0010977900004"></graphic></fig><table-wrap position="float" id="t1"><label>TABLE 1.</label><caption><p>IC<sub>50</sub>s and 95% CIs of NA activities against human influenza viruses<xref ref-type="table-fn" rid="t1fn3"><italic>c</italic></xref></p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Influenza virus<xref ref-type="table-fn" rid="t1fn1"><italic>a</italic></xref></th><th colspan="1" rowspan="2" align="center" valign="middle">Virus subtype or lineage</th><th colspan="1" rowspan="2" align="center" valign="middle">Strain type<xref ref-type="table-fn" rid="t1fn2"><italic>b</italic></xref></th><th colspan="2" rowspan="1" align="center" valign="bottom">CS-8958
<hr></hr></th><th colspan="2" rowspan="1" align="center" valign="bottom">R-125489
<hr></hr></th><th colspan="2" rowspan="1" align="center" valign="bottom">Zanamivir
<hr></hr></th><th colspan="2" rowspan="1" align="center" valign="bottom">Oseltamivir carboxylate
<hr></hr></th></tr><tr><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">H1N1 viruses</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Puerto Rico/8/1934</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">LS</td><td colspan="1" rowspan="1" align="center" valign="top">931</td><td colspan="1" rowspan="1" align="center" valign="top">829-1,050</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>5.97</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">4.88-7.69</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>3.62</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">3.08-4.30</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>2.39</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">1.96-2.95</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Yamagata/32/1989</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">882</td><td colspan="1" rowspan="1" align="center" valign="top">776-998</td><td colspan="1" rowspan="1" align="center" valign="top">3.42</td><td colspan="1" rowspan="1" align="center" valign="top">2.94-4.01</td><td colspan="1" rowspan="1" align="center" valign="top">2.55</td><td colspan="1" rowspan="1" align="center" valign="top">1.96-3.67</td><td colspan="1" rowspan="1" align="center" valign="top">1.54</td><td colspan="1" rowspan="1" align="center" valign="top">1.28-1.91</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/New Caledonia/20/1999</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">666</td><td colspan="1" rowspan="1" align="center" valign="top">589-756</td><td colspan="1" rowspan="1" align="center" valign="top">2.32</td><td colspan="1" rowspan="1" align="center" valign="top">1.85-2.95</td><td colspan="1" rowspan="1" align="center" valign="top">2.05</td><td colspan="1" rowspan="1" align="center" valign="top">1.68-2.65</td><td colspan="1" rowspan="1" align="center" valign="top">1.58</td><td colspan="1" rowspan="1" align="center" valign="top">1.35-1.90</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Shiga/1/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">733</td><td colspan="1" rowspan="1" align="center" valign="top">630-860</td><td colspan="1" rowspan="1" align="center" valign="top">2.09</td><td colspan="1" rowspan="1" align="center" valign="top">1.39-3.45</td><td colspan="1" rowspan="1" align="center" valign="top">1.63</td><td colspan="1" rowspan="1" align="center" valign="top">1.15-2.40</td><td colspan="1" rowspan="1" align="center" valign="top">1.34</td><td colspan="1" rowspan="1" align="center" valign="top">1.05-1.72</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Yamagata/3/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">709</td><td colspan="1" rowspan="1" align="center" valign="top">592-858</td><td colspan="1" rowspan="1" align="center" valign="top">2.57</td><td colspan="1" rowspan="1" align="center" valign="top">1.93-3.55</td><td colspan="1" rowspan="1" align="center" valign="top">1.68</td><td colspan="1" rowspan="1" align="center" valign="top">1.36-2.06</td><td colspan="1" rowspan="1" align="center" valign="top">1.08</td><td colspan="1" rowspan="1" align="center" valign="top">0.944-1.23</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Yamagata/57/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top"><underline>1,170</underline></td><td colspan="1" rowspan="1" align="center" valign="top">1,040-1,320</td><td colspan="1" rowspan="1" align="center" valign="top">1.65</td><td colspan="1" rowspan="1" align="center" valign="top">1.39-2.02</td><td colspan="1" rowspan="1" align="center" valign="top">1.14</td><td colspan="1" rowspan="1" align="center" valign="top">0.832-1.70</td><td colspan="1" rowspan="1" align="center" valign="top"><underline>0.658</underline></td><td colspan="1" rowspan="1" align="center" valign="top">0.575-0.756</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Saitama/78/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">940</td><td colspan="1" rowspan="1" align="center" valign="top">756-1,170</td><td colspan="1" rowspan="1" align="center" valign="top">1.79</td><td colspan="1" rowspan="1" align="center" valign="top">1.26-2.55</td><td colspan="1" rowspan="1" align="center" valign="top">1.38</td><td colspan="1" rowspan="1" align="center" valign="top">1.03-1.99</td><td colspan="1" rowspan="1" align="center" valign="top">1.12</td><td colspan="1" rowspan="1" align="center" valign="top">0.775-1.71</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Aichi/193/2004</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">983</td><td colspan="1" rowspan="1" align="center" valign="top">792-1,220</td><td colspan="1" rowspan="1" align="center" valign="top">2.63</td><td colspan="1" rowspan="1" align="center" valign="top">2.32-3.08</td><td colspan="1" rowspan="1" align="center" valign="top">1.17</td><td colspan="1" rowspan="1" align="center" valign="top">0.796-2.00</td><td colspan="1" rowspan="1" align="center" valign="top">1.26</td><td colspan="1" rowspan="1" align="center" valign="top">0.789-2.54</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Okinawa/42/2004</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>631</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">533-750</td><td colspan="1" rowspan="1" align="center" valign="top">2.07</td><td colspan="1" rowspan="1" align="center" valign="top">1.33-4.09</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>0.751</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">0.527-1.13</td><td colspan="1" rowspan="1" align="center" valign="top">1.86</td><td colspan="1" rowspan="1" align="center" valign="top">1.69-2.05</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Aichi/169/2005</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">664</td><td colspan="1" rowspan="1" align="center" valign="top">545-817</td><td colspan="1" rowspan="1" align="center" valign="top">1.55</td><td colspan="1" rowspan="1" align="center" valign="top">1.06-2.38</td><td colspan="1" rowspan="1" align="center" valign="top">1.19</td><td colspan="1" rowspan="1" align="center" valign="top">0.798-2.06</td><td colspan="1" rowspan="1" align="center" valign="top">1.12</td><td colspan="1" rowspan="1" align="center" valign="top">0.780-1.81</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Yamagata/83/2006</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">733</td><td colspan="1" rowspan="1" align="center" valign="top">668-808</td><td colspan="1" rowspan="1" align="center" valign="top"><underline>1.29</underline></td><td colspan="1" rowspan="1" align="center" valign="top">0.910-2.06</td><td colspan="1" rowspan="1" align="center" valign="top">0.880</td><td colspan="1" rowspan="1" align="center" valign="top">0.686-1.17</td><td colspan="1" rowspan="1" align="center" valign="top">0.785</td><td colspan="1" rowspan="1" align="center" valign="top">0.660-0.945</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Mean ± SD</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">822 ± 171</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">2.49 ± 1.30</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">1.64 ± 0.838</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">1.34 ± 0.491</td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">H2N2 virus</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Singapore/1/1957</td><td colspan="1" rowspan="1" align="left" valign="top">H2N2</td><td colspan="1" rowspan="1" align="left" valign="top">LS</td><td colspan="1" rowspan="1" align="center" valign="top">128</td><td colspan="1" rowspan="1" align="center" valign="top">107-152</td><td colspan="1" rowspan="1" align="center" valign="top">11.4</td><td colspan="1" rowspan="1" align="center" valign="top">9.14-14.4</td><td colspan="1" rowspan="1" align="center" valign="top">3.66</td><td colspan="1" rowspan="1" align="center" valign="top">2.98-4.56</td><td colspan="1" rowspan="1" align="center" valign="top">0.925</td><td colspan="1" rowspan="1" align="center" valign="top">0.831-1.03</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">H3N2 virus</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Aichi/2/1968</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">LS</td><td colspan="1" rowspan="1" align="center" valign="top">164</td><td colspan="1" rowspan="1" align="center" valign="top">149-179</td><td colspan="1" rowspan="1" align="center" valign="top">16.8</td><td colspan="1" rowspan="1" align="center" valign="top">13.9-21.1</td><td colspan="1" rowspan="1" align="center" valign="top">7.33</td><td colspan="1" rowspan="1" align="center" valign="top">5.75-10.2</td><td colspan="1" rowspan="1" align="center" valign="top">2.39</td><td colspan="1" rowspan="1" align="center" valign="top">1.83-3.48</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Kitakyushu/159/1993</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>221</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">205-239</td><td colspan="1" rowspan="1" align="center" valign="top">23.5</td><td colspan="1" rowspan="1" align="center" valign="top">18.9-31.3</td><td colspan="1" rowspan="1" align="center" valign="top">9.30</td><td colspan="1" rowspan="1" align="center" valign="top">8.40-10.3</td><td colspan="1" rowspan="1" align="center" valign="top">1.60</td><td colspan="1" rowspan="1" align="center" valign="top">1.14-2.60</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Wyoming/03/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">114</td><td colspan="1" rowspan="1" align="center" valign="top">99.5-129</td><td colspan="1" rowspan="1" align="center" valign="top">22.2</td><td colspan="1" rowspan="1" align="center" valign="top">17.9-28.0</td><td colspan="1" rowspan="1" align="center" valign="top">11.0</td><td colspan="1" rowspan="1" align="center" valign="top">9.50-12.9</td><td colspan="1" rowspan="1" align="center" valign="top">1.71</td><td colspan="1" rowspan="1" align="center" valign="top">1.34-2.34</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Wellington/1/2004</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">157</td><td colspan="1" rowspan="1" align="center" valign="top">132-183</td><td colspan="1" rowspan="1" align="center" valign="top">26.8</td><td colspan="1" rowspan="1" align="center" valign="top">23.9-30.9</td><td colspan="1" rowspan="1" align="center" valign="top">8.74</td><td colspan="1" rowspan="1" align="center" valign="top">7.47-10.2</td><td colspan="1" rowspan="1" align="center" valign="top">1.99</td><td colspan="1" rowspan="1" align="center" valign="top">1.92-2.06</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/California/07/2004</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">135</td><td colspan="1" rowspan="1" align="center" valign="top">121-150</td><td colspan="1" rowspan="1" align="center" valign="top">19.4</td><td colspan="1" rowspan="1" align="center" valign="top">15.7-25.6</td><td colspan="1" rowspan="1" align="center" valign="top">8.21</td><td colspan="1" rowspan="1" align="center" valign="top">6.32-11.8</td><td colspan="1" rowspan="1" align="center" valign="top">1.90</td><td colspan="1" rowspan="1" align="center" valign="top">1.47-2.69</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/New York/55/2004</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">136</td><td colspan="1" rowspan="1" align="center" valign="top">125-147</td><td colspan="1" rowspan="1" align="center" valign="top">19.2</td><td colspan="1" rowspan="1" align="center" valign="top">15.3-25.9</td><td colspan="1" rowspan="1" align="center" valign="top">7.35</td><td colspan="1" rowspan="1" align="center" valign="top">5.68-10.5</td><td colspan="1" rowspan="1" align="center" valign="top">1.56</td><td colspan="1" rowspan="1" align="center" valign="top">1.18-2.28</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Hiroshima/52/2005</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">69.1</td><td colspan="1" rowspan="1" align="center" valign="top">62.5-76.7</td><td colspan="1" rowspan="1" align="center" valign="top">12.7</td><td colspan="1" rowspan="1" align="center" valign="top">11.1-14.6</td><td colspan="1" rowspan="1" align="center" valign="top">5.11</td><td colspan="1" rowspan="1" align="center" valign="top">4.32-6.24</td><td colspan="1" rowspan="1" align="center" valign="top">1.33</td><td colspan="1" rowspan="1" align="center" valign="top">1.18-1.51</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Wisconsin/67/2005</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">187</td><td colspan="1" rowspan="1" align="center" valign="top">171-206</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>38.8</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">33.4-45.5</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>14.2</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">11.9-17.2</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>3.44</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">3.16-3.75</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Shiga/5/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">64.2</td><td colspan="1" rowspan="1" align="center" valign="top">51.5-78.9</td><td colspan="1" rowspan="1" align="center" valign="top">10.1</td><td colspan="1" rowspan="1" align="center" valign="top">9.29-11.0</td><td colspan="1" rowspan="1" align="center" valign="top">4.82</td><td colspan="1" rowspan="1" align="center" valign="top">4.06-5.88</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>0.706</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">0.597-0.843</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Yamagata/1/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">56.6</td><td colspan="1" rowspan="1" align="center" valign="top">45.5-69.1</td><td colspan="1" rowspan="1" align="center" valign="top">14.2</td><td colspan="1" rowspan="1" align="center" valign="top">12.2-16.6</td><td colspan="1" rowspan="1" align="center" valign="top">7.58</td><td colspan="1" rowspan="1" align="center" valign="top">6.07-10.1</td><td colspan="1" rowspan="1" align="center" valign="top">1.09</td><td colspan="1" rowspan="1" align="center" valign="top">0.981-1.22</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Yamagata/2/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">46.6</td><td colspan="1" rowspan="1" align="center" valign="top">40.8-53.0</td><td colspan="1" rowspan="1" align="center" valign="top"><underline>7.09</underline></td><td colspan="1" rowspan="1" align="center" valign="top">5.36-9.62</td><td colspan="1" rowspan="1" align="center" valign="top">6.45</td><td colspan="1" rowspan="1" align="center" valign="top">5.08-8.87</td><td colspan="1" rowspan="1" align="center" valign="top">0.981</td><td colspan="1" rowspan="1" align="center" valign="top">0.880-1.09</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Saitama/80/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>39.2</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">31.5-48.0</td><td colspan="1" rowspan="1" align="center" valign="top">10.4</td><td colspan="1" rowspan="1" align="center" valign="top">7.57-15.3</td><td colspan="1" rowspan="1" align="center" valign="top">7.16</td><td colspan="1" rowspan="1" align="center" valign="top">4.86-13.8</td><td colspan="1" rowspan="1" align="center" valign="top">0.711</td><td colspan="1" rowspan="1" align="center" valign="top">0.550-0.940</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Osaka/56/2004</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">129</td><td colspan="1" rowspan="1" align="center" valign="top">118-141</td><td colspan="1" rowspan="1" align="center" valign="top">8.72</td><td colspan="1" rowspan="1" align="center" valign="top">6.96-11.2</td><td colspan="1" rowspan="1" align="center" valign="top">4.84</td><td colspan="1" rowspan="1" align="center" valign="top">4.07-5.93</td><td colspan="1" rowspan="1" align="center" valign="top">1.08</td><td colspan="1" rowspan="1" align="center" valign="top">0.836-1.48</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Tokushima/1/2005</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">131</td><td colspan="1" rowspan="1" align="center" valign="top">117-147</td><td colspan="1" rowspan="1" align="center" valign="top">7.54</td><td colspan="1" rowspan="1" align="center" valign="top">5.76-11.0</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>3.42</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">3.02-3.88</td><td colspan="1" rowspan="1" align="center" valign="top">0.925</td><td colspan="1" rowspan="1" align="center" valign="top">0.742-1.19</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> A/Saitama/07/2006</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">63.3</td><td colspan="1" rowspan="1" align="center" valign="top">52.8-75.0</td><td colspan="1" rowspan="1" align="center" valign="top">13.0</td><td colspan="1" rowspan="1" align="center" valign="top">11.2-15.3</td><td colspan="1" rowspan="1" align="center" valign="top">6.04</td><td colspan="1" rowspan="1" align="center" valign="top">5.01-7.62</td><td colspan="1" rowspan="1" align="center" valign="top">0.885</td><td colspan="1" rowspan="1" align="center" valign="top">0.716-1.12</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Mean ± SD</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">114 ± 55.5</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">16.7 ± 8.62</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">7.44 ± 2.70</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">1.49 ± 0.738</td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">Type B</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Brisbane/32/2002</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">9,890</td><td colspan="1" rowspan="1" align="center" valign="top">8,880-11,000</td><td colspan="1" rowspan="1" align="center" valign="top">30.5</td><td colspan="1" rowspan="1" align="center" valign="top">26.2-35.5</td><td colspan="1" rowspan="1" align="center" valign="top">7.78</td><td colspan="1" rowspan="1" align="center" valign="top">6.29-9.83</td><td colspan="1" rowspan="1" align="center" valign="top">13.6</td><td colspan="1" rowspan="1" align="center" valign="top">12.2-15.1</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Malaysia/2506/2004</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">11,100</td><td colspan="1" rowspan="1" align="center" valign="top">10,400-11,900</td><td colspan="1" rowspan="1" align="center" valign="top">31.3</td><td colspan="1" rowspan="1" align="center" valign="top">28.7-34.0</td><td colspan="1" rowspan="1" align="center" valign="top">8.66</td><td colspan="1" rowspan="1" align="center" valign="top">6.94-11.1</td><td colspan="1" rowspan="1" align="center" valign="top">15.1</td><td colspan="1" rowspan="1" align="center" valign="top">13.6-16.7</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Ohio/01/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">12,800</td><td colspan="1" rowspan="1" align="center" valign="top">11,800-13,900</td><td colspan="1" rowspan="1" align="center" valign="top">30.0</td><td colspan="1" rowspan="1" align="center" valign="top">27.6-32.7</td><td colspan="1" rowspan="1" align="center" valign="top">7.86</td><td colspan="1" rowspan="1" align="center" valign="top">6.45-9.75</td><td colspan="1" rowspan="1" align="center" valign="top">13.6</td><td colspan="1" rowspan="1" align="center" valign="top">11.9-15.5</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Shiga/17/2002</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">7,680</td><td colspan="1" rowspan="1" align="center" valign="top">6,980-8,490</td><td colspan="1" rowspan="1" align="center" valign="top">18.2</td><td colspan="1" rowspan="1" align="center" valign="top">16.9-19.6</td><td colspan="1" rowspan="1" align="center" valign="top">7.11</td><td colspan="1" rowspan="1" align="center" valign="top">5.45-10.3</td><td colspan="1" rowspan="1" align="center" valign="top">8.72</td><td colspan="1" rowspan="1" align="center" valign="top">5.99-11.8</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/15/2002</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">6,980</td><td colspan="1" rowspan="1" align="center" valign="top">6,310-7,760</td><td colspan="1" rowspan="1" align="center" valign="top">15.9</td><td colspan="1" rowspan="1" align="center" valign="top">13.6-19.2</td><td colspan="1" rowspan="1" align="center" valign="top">5.68</td><td colspan="1" rowspan="1" align="center" valign="top">4.48-7.72</td><td colspan="1" rowspan="1" align="center" valign="top">7.25</td><td colspan="1" rowspan="1" align="center" valign="top">5.81-8.94</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Akita/9/2003</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">13,800</td><td colspan="1" rowspan="1" align="center" valign="top">12,400-15,600</td><td colspan="1" rowspan="1" align="center" valign="top">12.4</td><td colspan="1" rowspan="1" align="center" valign="top">10.8-14.5</td><td colspan="1" rowspan="1" align="center" valign="top">3.79</td><td colspan="1" rowspan="1" align="center" valign="top">3.35-4.33</td><td colspan="1" rowspan="1" align="center" valign="top">9.55</td><td colspan="1" rowspan="1" align="center" valign="top">8.04-11.3</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Tokushima/1/2003</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">13,800</td><td colspan="1" rowspan="1" align="center" valign="top">12,600-15,200</td><td colspan="1" rowspan="1" align="center" valign="top">11.4</td><td colspan="1" rowspan="1" align="center" valign="top">10.1-13.0</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><bold>3.55</bold></underline></td><td colspan="1" rowspan="1" align="center" valign="top">3.12-4.07</td><td colspan="1" rowspan="1" align="center" valign="top">9.26</td><td colspan="1" rowspan="1" align="center" valign="top">7.77-11.0</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/145/2003</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">15,900</td><td colspan="1" rowspan="1" align="center" valign="top">13,900-18,300</td><td colspan="1" rowspan="1" align="center" valign="top"><bold><underline>10.4</underline></bold></td><td colspan="1" rowspan="1" align="center" valign="top">7.86-14.7</td><td colspan="1" rowspan="1" align="center" valign="top">4.05</td><td colspan="1" rowspan="1" align="center" valign="top">3.44-4.84</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><bold>3.09</bold></underline></td><td colspan="1" rowspan="1" align="center" valign="top">2.83-3.37</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/398/2003</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">12,400</td><td colspan="1" rowspan="1" align="center" valign="top">11,700-13,200</td><td colspan="1" rowspan="1" align="center" valign="top">12.5</td><td colspan="1" rowspan="1" align="center" valign="top">11.1-14.2</td><td colspan="1" rowspan="1" align="center" valign="top">3.78</td><td colspan="1" rowspan="1" align="center" valign="top">3.33-4.32</td><td colspan="1" rowspan="1" align="center" valign="top">10.1</td><td colspan="1" rowspan="1" align="center" valign="top">8.53-12.0</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Aichi/3/2006</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">13,800</td><td colspan="1" rowspan="1" align="center" valign="top">12,900-14,900</td><td colspan="1" rowspan="1" align="center" valign="top">19.3</td><td colspan="1" rowspan="1" align="center" valign="top">16.0-24.4</td><td colspan="1" rowspan="1" align="center" valign="top">4.85</td><td colspan="1" rowspan="1" align="center" valign="top">4.19-5.71</td><td colspan="1" rowspan="1" align="center" valign="top">12.4</td><td colspan="1" rowspan="1" align="center" valign="top">11.0-14.0</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Saitama/01/2006</td><td colspan="1" rowspan="1" align="left" valign="top">Victoria</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>45,500</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">42,000-49,800</td><td colspan="1" rowspan="1" align="center" valign="top"><bold>26.5</bold></td><td colspan="1" rowspan="1" align="center" valign="top">19.9-40.2</td><td colspan="1" rowspan="1" align="center" valign="top">6.41</td><td colspan="1" rowspan="1" align="center" valign="top">5.16-8.46</td><td colspan="1" rowspan="1" align="center" valign="top"><bold>13.7</bold></td><td colspan="1" rowspan="1" align="center" valign="top">11.7-16.0</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Mie/1/1993</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">6,850</td><td colspan="1" rowspan="1" align="center" valign="top">6,150-7,610</td><td colspan="1" rowspan="1" align="center" valign="top">31.3</td><td colspan="1" rowspan="1" align="center" valign="top">28.2-34.8</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>12.0</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">10.6-13.6</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>15.6</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">14.2-17.1</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Shanghai/361/2002</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">VS</td><td colspan="1" rowspan="1" align="center" valign="top">6,660</td><td colspan="1" rowspan="1" align="center" valign="top">5,920-7,470</td><td colspan="1" rowspan="1" align="center" valign="top"><underline>31.4</underline></td><td colspan="1" rowspan="1" align="center" valign="top">28.6-34.6</td><td colspan="1" rowspan="1" align="center" valign="top">10.1</td><td colspan="1" rowspan="1" align="center" valign="top">7.76-13.9</td><td colspan="1" rowspan="1" align="center" valign="top">12.0</td><td colspan="1" rowspan="1" align="center" valign="top">10.5-13.6</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Shiga/31/2002</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">10,500</td><td colspan="1" rowspan="1" align="center" valign="top">10,000-11,100</td><td colspan="1" rowspan="1" align="center" valign="top">14.0</td><td colspan="1" rowspan="1" align="center" valign="top">12.1-16.4</td><td colspan="1" rowspan="1" align="center" valign="top">4.90</td><td colspan="1" rowspan="1" align="center" valign="top">4.08-6.08</td><td colspan="1" rowspan="1" align="center" valign="top">9.16</td><td colspan="1" rowspan="1" align="center" valign="top">7.61-11.0</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Shizuoka/58/2004</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">7,530</td><td colspan="1" rowspan="1" align="center" valign="top">6,850-8,310</td><td colspan="1" rowspan="1" align="center" valign="top">16.0</td><td colspan="1" rowspan="1" align="center" valign="top">13.6-19.4</td><td colspan="1" rowspan="1" align="center" valign="top">5.67</td><td colspan="1" rowspan="1" align="center" valign="top">4.66-7.24</td><td colspan="1" rowspan="1" align="center" valign="top">8.34</td><td colspan="1" rowspan="1" align="center" valign="top">7.06-9.81</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/85/2004</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">7,190</td><td colspan="1" rowspan="1" align="center" valign="top">6,610-7,830</td><td colspan="1" rowspan="1" align="center" valign="top">18.3</td><td colspan="1" rowspan="1" align="center" valign="top">15.4-22.7</td><td colspan="1" rowspan="1" align="center" valign="top">6.44</td><td colspan="1" rowspan="1" align="center" valign="top">5.25-8.33</td><td colspan="1" rowspan="1" align="center" valign="top">8.84</td><td colspan="1" rowspan="1" align="center" valign="top">7.51-10.4</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/87/2004</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">7,790</td><td colspan="1" rowspan="1" align="center" valign="top">7,470-8,110</td><td colspan="1" rowspan="1" align="center" valign="top">16.7</td><td colspan="1" rowspan="1" align="center" valign="top">14.0-20.4</td><td colspan="1" rowspan="1" align="center" valign="top">5.82</td><td colspan="1" rowspan="1" align="center" valign="top">4.86-7.26</td><td colspan="1" rowspan="1" align="center" valign="top">8.26</td><td colspan="1" rowspan="1" align="center" valign="top">6.95-9.78</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Aichi/186/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">3,550</td><td colspan="1" rowspan="1" align="center" valign="top">3,160-3,980</td><td colspan="1" rowspan="1" align="center" valign="top">15.0</td><td colspan="1" rowspan="1" align="center" valign="top">12.8-18.1</td><td colspan="1" rowspan="1" align="center" valign="top">6.72</td><td colspan="1" rowspan="1" align="center" valign="top">5.45-8.79</td><td colspan="1" rowspan="1" align="center" valign="top">9.21</td><td colspan="1" rowspan="1" align="center" valign="top">8.02-10.6</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Saitama/01/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">3,610</td><td colspan="1" rowspan="1" align="center" valign="top">3,200-4,080</td><td colspan="1" rowspan="1" align="center" valign="top">15.0</td><td colspan="1" rowspan="1" align="center" valign="top">13.2-17.5</td><td colspan="1" rowspan="1" align="center" valign="top">6.89</td><td colspan="1" rowspan="1" align="center" valign="top">5.49-9.28</td><td colspan="1" rowspan="1" align="center" valign="top">10.6</td><td colspan="1" rowspan="1" align="center" valign="top">9.25-12.2</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Sapporo/29/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">3,600</td><td colspan="1" rowspan="1" align="center" valign="top">3,140-4,120</td><td colspan="1" rowspan="1" align="center" valign="top">15.4</td><td colspan="1" rowspan="1" align="center" valign="top">13.3-18.2</td><td colspan="1" rowspan="1" align="center" valign="top">6.91</td><td colspan="1" rowspan="1" align="center" valign="top">5.40-9.64</td><td colspan="1" rowspan="1" align="center" valign="top">9.62</td><td colspan="1" rowspan="1" align="center" valign="top">8.27-11.2</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Tokushima/1/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">3,710</td><td colspan="1" rowspan="1" align="center" valign="top">3,260-4,240</td><td colspan="1" rowspan="1" align="center" valign="top">14.2</td><td colspan="1" rowspan="1" align="center" valign="top">12.2-16.8</td><td colspan="1" rowspan="1" align="center" valign="top">6.30</td><td colspan="1" rowspan="1" align="center" valign="top">5.18-8.04</td><td colspan="1" rowspan="1" align="center" valign="top">8.35</td><td colspan="1" rowspan="1" align="center" valign="top">7.16-9.71</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/1/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top">3,630</td><td colspan="1" rowspan="1" align="center" valign="top">3,190-4,140</td><td colspan="1" rowspan="1" align="center" valign="top">13.7</td><td colspan="1" rowspan="1" align="center" valign="top">11.9-16.2</td><td colspan="1" rowspan="1" align="center" valign="top">6.36</td><td colspan="1" rowspan="1" align="center" valign="top">5.11-8.45</td><td colspan="1" rowspan="1" align="center" valign="top">9.44</td><td colspan="1" rowspan="1" align="center" valign="top">7.86-11.3</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> B/Yamagata/113/2005</td><td colspan="1" rowspan="1" align="left" valign="top">Yamagata</td><td colspan="1" rowspan="1" align="left" valign="top">CI</td><td colspan="1" rowspan="1" align="center" valign="top"><underline><underline>3,500</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">3,130-3,910</td><td colspan="1" rowspan="1" align="center" valign="top">15.8</td><td colspan="1" rowspan="1" align="center" valign="top">13.5-19.0</td><td colspan="1" rowspan="1" align="center" valign="top"><bold>7.59</bold></td><td colspan="1" rowspan="1" align="center" valign="top">5.91-10.7</td><td colspan="1" rowspan="1" align="center" valign="top">10.6</td><td colspan="1" rowspan="1" align="center" valign="top">9.17-12.3</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"> Mean ± SD</td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">10,100 ± 8,670</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">18.9 ± 7.20</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">6.49 ± 2.02</td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top">10.3 ± 2.82</td><td colspan="1" rowspan="1" align="center" valign="top"></td></tr></tbody></table><table-wrap-foot><fn id="t1fn1"><label>a</label><p>Means and standard deviations (SD) of NA inhibitor compound IC<sub>50</sub>s to H1N1 (11 strains), H3N2 (15 strains), and type B viruses (23 strains) are shown.</p></fn><fn id="t1fn2"><label>b</label><p>LS, laboratory strain; VS, vaccine strain; CI, clinical isolate.</p></fn><fn id="t1fn3"><label>c</label><p>Maximum and minimum IC<sub>50</sub>s of each compound against H1N1, H3N2, and type B viruses are underlined. IC<sub>50</sub>s of NA inhibitors to B viruses in boldface indicate maximum or minimum IC<sub>50</sub>s of each inhibitor to the clinical isolates. CI, confidence interval.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t2"><label>TABLE 2.</label><caption><p>IC<sub>50</sub>s and 95% CIs of NA activities against animal influenza viruses<xref ref-type="table-fn" rid="t2fn2"><italic>b</italic></xref></p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Influenza virus</th><th colspan="1" rowspan="2" align="center" valign="middle">Subtype</th><th colspan="2" rowspan="1" align="center" valign="bottom">CS-8958
<hr></hr></th><th colspan="2" rowspan="1" align="center" valign="bottom">R-125489
<hr></hr></th><th colspan="2" rowspan="1" align="center" valign="bottom">Zanamivir
<hr></hr></th><th colspan="2" rowspan="1" align="center" valign="bottom">Oseltamivir carboxylate
<hr></hr></th></tr><tr><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">A/R(duck/Mongolia/54/01- duck/Mongolia/47/01)<xref ref-type="table-fn" rid="t2fn1"><italic>a</italic></xref></td><td colspan="1" rowspan="1" align="left" valign="top">H5N1</td><td colspan="1" rowspan="1" align="char" char="." valign="top">276</td><td colspan="1" rowspan="1" align="center" valign="top">254-300</td><td colspan="1" rowspan="1" align="char" char="." valign="top">4.54</td><td colspan="1" rowspan="1" align="center" valign="top">3.91-5.37</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.99</td><td colspan="1" rowspan="1" align="center" valign="top">2.25-4.20</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.17</td><td colspan="1" rowspan="1" align="center" valign="top">1.94-2.43</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/duck/Hokkaido/84/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H5N3</td><td colspan="1" rowspan="1" align="char" char="." valign="top">456</td><td colspan="1" rowspan="1" align="center" valign="top">413-502</td><td colspan="1" rowspan="1" align="char" char="." valign="top">13.3</td><td colspan="1" rowspan="1" align="center" valign="top">11.6-15.6</td><td colspan="1" rowspan="1" align="char" char="." valign="top">3.65</td><td colspan="1" rowspan="1" align="center" valign="top">2.63-5.57</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.94</td><td colspan="1" rowspan="1" align="center" valign="top">2.80-3.10</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/turkey/Ontario/6,118/1968</td><td colspan="1" rowspan="1" align="left" valign="top">H8N4</td><td colspan="1" rowspan="1" align="char" char="." valign="top">420</td><td colspan="1" rowspan="1" align="center" valign="top">378-471</td><td colspan="1" rowspan="1" align="char" char="." valign="top">7.08</td><td colspan="1" rowspan="1" align="center" valign="top">6.55-7.71</td><td colspan="1" rowspan="1" align="char" char="." valign="top">5.58</td><td colspan="1" rowspan="1" align="center" valign="top">4.35-7.71</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline>3.65</underline></td><td colspan="1" rowspan="1" align="center" valign="top">2.99-4.37</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/duck/Alberta/60/1976</td><td colspan="1" rowspan="1" align="left" valign="top">H12N5</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline><underline>1,140</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">1,020-1,270</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.34</td><td colspan="1" rowspan="1" align="center" valign="top">2.24-2.44</td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.83</td><td colspan="1" rowspan="1" align="center" valign="top">1.49-2.35</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline><underline>1.43</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">1.31-1.55</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/duck/England/1/1956</td><td colspan="1" rowspan="1" align="left" valign="top">H11N6</td><td colspan="1" rowspan="1" align="char" char="." valign="top">262</td><td colspan="1" rowspan="1" align="center" valign="top">242-282</td><td colspan="1" rowspan="1" align="char" char="." valign="top">25.5</td><td colspan="1" rowspan="1" align="center" valign="top">24.9-26.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top">8.57</td><td colspan="1" rowspan="1" align="center" valign="top">8.11-9.06</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.81</td><td colspan="1" rowspan="1" align="center" valign="top">2.70-2.92</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/seal/Massachusetts/1/1980</td><td colspan="1" rowspan="1" align="left" valign="top">H7N7</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline><underline>142</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">121-165</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline><underline>27.9</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">25.9-30.1</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline>11.5</underline></td><td colspan="1" rowspan="1" align="center" valign="top">10.5-12.6</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.56</td><td colspan="1" rowspan="1" align="center" valign="top">2.42-2.72</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/duck/Ukraine/1/1963</td><td colspan="1" rowspan="1" align="left" valign="top">H3N8</td><td colspan="1" rowspan="1" align="char" char="." valign="top">1,050</td><td colspan="1" rowspan="1" align="center" valign="top">1,010-1,090</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline><underline>1.81</underline></underline></td><td colspan="1" rowspan="1" align="center" valign="top">1.77-1.84</td><td colspan="1" rowspan="1" align="char" char="." valign="top"><underline>1.40</underline></td><td colspan="1" rowspan="1" align="center" valign="top">1.24-1.61</td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.12</td><td colspan="1" rowspan="1" align="center" valign="top">1.93-2.34</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/duck/Memphis/546/1974</td><td colspan="1" rowspan="1" align="left" valign="top">H11N9</td><td colspan="1" rowspan="1" align="char" char="." valign="top">356</td><td colspan="1" rowspan="1" align="center" valign="top">313-403</td><td colspan="1" rowspan="1" align="char" char="." valign="top">6.81</td><td colspan="1" rowspan="1" align="center" valign="top">6.51-7.14</td><td colspan="1" rowspan="1" align="char" char="." valign="top">3.31</td><td colspan="1" rowspan="1" align="center" valign="top">3.11-3.53</td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.70</td><td colspan="1" rowspan="1" align="center" valign="top">1.66-1.73</td></tr></tbody></table><table-wrap-foot><fn id="t2fn1"><label>a</label><p>Reassortant virus generated from A/duck/Mongolia/54/01 (H5N2) and A/duck/Mongolia/47/01 (H7N1).</p></fn><fn id="t2fn2"><label>b</label><p>Maximum and minimum IC<sub>50</sub>s are underlined for each compound. CI, confidence interval.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t3"><label>TABLE 3.</label><caption><p>IC<sub>50</sub>s, 95% CIs, and mutant/wild-type ratios of NA activities against oseltamivir-resistant influenza viruses<xref ref-type="table-fn" rid="t3fn2"><italic>b</italic></xref></p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="1" rowspan="2" align="center" valign="middle">Influenza virus</th><th colspan="1" rowspan="2" align="center" valign="middle">Virus type or subtype</th><th colspan="1" rowspan="2" align="center" valign="middle">Mutation in NA<xref ref-type="table-fn" rid="t3fn1"><italic>a</italic></xref></th><th colspan="3" rowspan="1" align="center" valign="bottom">R-125489
<hr></hr></th><th colspan="3" rowspan="1" align="center" valign="bottom">Zanamivir
<hr></hr></th><th colspan="3" rowspan="1" align="center" valign="bottom">Oseltamivir carboxylate
<hr></hr></th></tr><tr><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">Ratio</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">Ratio</th><th colspan="1" rowspan="1" align="center" valign="bottom">IC<sub>50</sub> (nM)</th><th colspan="1" rowspan="1" align="center" valign="bottom">95% CI</th><th colspan="1" rowspan="1" align="center" valign="bottom">Ratio</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Yokohama/67/2006 (clone 1)</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">WT</td><td colspan="1" rowspan="1" align="char" char="." valign="top">3.03</td><td colspan="1" rowspan="1" align="center" valign="top">2.75-3.35</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.70</td><td colspan="1" rowspan="1" align="center" valign="top">2.53-2.90</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.28</td><td colspan="1" rowspan="1" align="center" valign="top">2.12-2.43</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.9</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.1</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">330</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Yokohama/67/2006 H274Y (clone 11)</td><td colspan="1" rowspan="1" align="left" valign="top">H1N1</td><td colspan="1" rowspan="1" align="left" valign="top">H274Y</td><td colspan="1" rowspan="1" align="char" char="." valign="top">5.62</td><td colspan="1" rowspan="1" align="center" valign="top">4.75-6.89</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">3.05</td><td colspan="1" rowspan="1" align="center" valign="top">2.88-3.23</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">755</td><td colspan="1" rowspan="1" align="center" valign="top">727-784</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Kawasaki/IMS22A-954/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">WT</td><td colspan="1" rowspan="1" align="char" char="." valign="top">15.4</td><td colspan="1" rowspan="1" align="center" valign="top">13.4-18.0</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">8.29</td><td colspan="1" rowspan="1" align="center" valign="top">7.87-8.72</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.25</td><td colspan="1" rowspan="1" align="center" valign="top">1.09-1.45</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">0.69</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">8,400</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Kawasaki/IMS22B-955/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">R292K</td><td colspan="1" rowspan="1" align="char" char="." valign="top">10.6</td><td colspan="1" rowspan="1" align="center" valign="top">9.83-11.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">11.2</td><td colspan="1" rowspan="1" align="center" valign="top">9.59-13.0</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">10,400</td><td colspan="1" rowspan="1" align="center" valign="top">9,600-11,400</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Yokohama/IMS9A-2029/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">WT</td><td colspan="1" rowspan="1" align="char" char="." valign="top">19.2</td><td colspan="1" rowspan="1" align="center" valign="top">15.9-24.2</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">10.7</td><td colspan="1" rowspan="1" align="center" valign="top">10.1-11.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.78</td><td colspan="1" rowspan="1" align="center" valign="top">1.76-1.80</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">0.69</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">0.72</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">79</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Yokohama/IMS9B-2050/2003</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">E119V</td><td colspan="1" rowspan="1" align="char" char="." valign="top">13.2</td><td colspan="1" rowspan="1" align="center" valign="top">11.7-15.0</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">7.71</td><td colspan="1" rowspan="1" align="center" valign="top">7.58-7.85</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">140</td><td colspan="1" rowspan="1" align="center" valign="top">120-165</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Kawasaki/MS31A-1030/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">WT</td><td colspan="1" rowspan="1" align="char" char="." valign="top">13.4</td><td colspan="1" rowspan="1" align="center" valign="top">11.8-15.3</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">7.82</td><td colspan="1" rowspan="1" align="center" valign="top">7.57-8.10</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.18</td><td colspan="1" rowspan="1" align="center" valign="top">1.07-1.31</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="left" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">2.8</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">1.7</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="center" valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">32</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">A/Kawasaki/MS31B-1206/2002</td><td colspan="1" rowspan="1" align="left" valign="top">H3N2</td><td colspan="1" rowspan="1" align="left" valign="top">N294S</td><td colspan="1" rowspan="1" align="char" char="." valign="top">37.3</td><td colspan="1" rowspan="1" align="center" valign="top">33.9-41.2</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">13.5</td><td colspan="1" rowspan="1" align="center" valign="top">12.0-15.4</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td><td colspan="1" rowspan="1" align="char" char="." valign="top">37.2</td><td colspan="1" rowspan="1" align="center" valign="top">34.7-39.7</td><td colspan="1" rowspan="1" align="char" char="." valign="top"></td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">B/Yokohama/UT2203/2005</td><td colspan="1" rowspan="1" align="left" valign="top">B</td><td colspan="1" rowspan="1" align="left" valign="top">D198N</td><td colspan="1" rowspan="1" align="char" char="." valign="top">48.9</td><td colspan="1" rowspan="1" align="center" valign="top">41.7-58.7</td><td colspan="1" rowspan="1" align="center" valign="top">—</td><td colspan="1" rowspan="1" align="char" char="." valign="top">33.6</td><td colspan="1" rowspan="1" align="center" valign="top">31.6-35.8</td><td colspan="1" rowspan="1" align="center" valign="top">—</td><td colspan="1" rowspan="1" align="char" char="." valign="top">40.5</td><td colspan="1" rowspan="1" align="center" valign="top">36.8-44.6</td><td colspan="1" rowspan="1" align="center" valign="top">—</td></tr><tr><td colspan="1" rowspan="1" align="left" valign="top">B/Yokohama/UT3318/2005</td><td colspan="1" rowspan="1" align="left" valign="top">B</td><td colspan="1" rowspan="1" align="left" valign="top">I222T</td><td colspan="1" rowspan="1" align="char" char="." valign="top">30.2</td><td colspan="1" rowspan="1" align="center" valign="top">27.6-33.0</td><td colspan="1" rowspan="1" align="center" valign="top">—</td><td colspan="1" rowspan="1" align="char" char="." valign="top">20.0</td><td colspan="1" rowspan="1" align="center" valign="top">16.2-26.4</td><td colspan="1" rowspan="1" align="center" valign="top">—</td><td colspan="1" rowspan="1" align="char" char="." valign="top">68.8</td><td colspan="1" rowspan="1" align="center" valign="top">63.8-74.1</td><td colspan="1" rowspan="1" align="center" valign="top">—</td></tr></tbody></table><table-wrap-foot><fn id="t3fn1"><label>a</label><p>Amino acids at left mutated to the amino acids at right at the indicated residue numbers, based on N2 NA numbering. Amino acids are described using one-letter symbols. WT, wild type.</p></fn><fn id="t3fn2"><label>b</label><p>Mutant/wild-type IC<sub>50</sub> ratios are shown. CI, confidence interval; —, not applicable.</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc><affiliations><list><country><li>Japon</li></country><region><li>Région de Kantō</li></region><settlement><li>Tokyo</li></settlement></list><tree><country name="Japon"><region name="Région de Kantō"><name sortKey="Yamashita, Makoto" sort="Yamashita, Makoto" uniqKey="Yamashita M" first="Makoto" last="Yamashita">Makoto Yamashita</name></region><name sortKey="Kakuta, Masayo" sort="Kakuta, Masayo" uniqKey="Kakuta M" first="Masayo" last="Kakuta">Masayo Kakuta</name><name sortKey="Kubo, Shuku" sort="Kubo, Shuku" uniqKey="Kubo S" first="Shuku" last="Kubo">Shuku Kubo</name><name sortKey="Nasu, Hatsumi" sort="Nasu, Hatsumi" uniqKey="Nasu H" first="Hatsumi" last="Nasu">Hatsumi Nasu</name><name sortKey="Tokumitsu, Akane" sort="Tokumitsu, Akane" uniqKey="Tokumitsu A" first="Akane" last="Tokumitsu">Akane Tokumitsu</name><name sortKey="Tomozawa, Takanori" sort="Tomozawa, Takanori" uniqKey="Tomozawa T" first="Takanori" last="Tomozawa">Takanori Tomozawa</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Pmc/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000B36 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd -nk 000B36 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= H2N2V1
|flux= Pmc
|étape= Checkpoint
|type= RBID
|clé= PMC:2612152
|texte= CS-8958, a Prodrug of the New Neuraminidase Inhibitor R-125489, Shows Long-Acting Anti-Influenza Virus Activity▿
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/RBID.i -Sk "pubmed:18955520" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a H2N2V1
| This area was generated with Dilib version V0.6.33. |  |