Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.
Identifieur interne : 001F96 ( PubMed/Corpus ); précédent : 001F95; suivant : 001F97Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.
Auteurs : Robert A. Hauser ; Lisa M. Shulman ; Joel M. Trugman ; John W. Roberts ; Akihisa Mori ; Rocco Ballerini ; Neil M. SussmanSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2008.
English descriptors
- KwdEn :
- Aged, Analysis of Variance, Antiparkinson Agents (therapeutic use), Double-Blind Method, Drug-Related Side Effects and Adverse Reactions, Dyskinesia, Drug-Induced (drug therapy), Dyskinesia, Drug-Induced (etiology), Female, Humans, Levodopa (adverse effects), Male, Middle Aged, Parkinson Disease (drug therapy), Parkinson Disease (physiopathology), Purines (therapeutic use), Questionnaires, Severity of Illness Index, Time Factors.
- MESH :
- chemical , adverse effects : Levodopa.
- chemical , therapeutic use : Antiparkinson Agents, Purines.
- drug therapy : Dyskinesia, Drug-Induced, Parkinson Disease.
- etiology : Dyskinesia, Drug-Induced.
- physiopathology : Parkinson Disease.
- Aged, Analysis of Variance, Double-Blind Method, Drug-Related Side Effects and Adverse Reactions, Female, Humans, Male, Middle Aged, Questionnaires, Severity of Illness Index, Time Factors.
Abstract
The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.
DOI: 10.1002/mds.22095
PubMed: 18831530
Links to Exploration step
pubmed:18831530Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.</title>
<author><name sortKey="Hauser, Robert A" sort="Hauser, Robert A" uniqKey="Hauser R" first="Robert A" last="Hauser">Robert A. Hauser</name>
<affiliation><nlm:affiliation>Department of Neurology, University of South Florida, Tampa, Florida 33606, USA. rhauser@health.usf.edu</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Shulman, Lisa M" sort="Shulman, Lisa M" uniqKey="Shulman L" first="Lisa M" last="Shulman">Lisa M. Shulman</name>
</author>
<author><name sortKey="Trugman, Joel M" sort="Trugman, Joel M" uniqKey="Trugman J" first="Joel M" last="Trugman">Joel M. Trugman</name>
</author>
<author><name sortKey="Roberts, John W" sort="Roberts, John W" uniqKey="Roberts J" first="John W" last="Roberts">John W. Roberts</name>
</author>
<author><name sortKey="Mori, Akihisa" sort="Mori, Akihisa" uniqKey="Mori A" first="Akihisa" last="Mori">Akihisa Mori</name>
</author>
<author><name sortKey="Ballerini, Rocco" sort="Ballerini, Rocco" uniqKey="Ballerini R" first="Rocco" last="Ballerini">Rocco Ballerini</name>
</author>
<author><name sortKey="Sussman, Neil M" sort="Sussman, Neil M" uniqKey="Sussman N" first="Neil M" last="Sussman">Neil M. Sussman</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2008">2008</date>
<idno type="doi">10.1002/mds.22095</idno>
<idno type="RBID">pubmed:18831530</idno>
<idno type="pmid">18831530</idno>
<idno type="wicri:Area/PubMed/Corpus">001F96</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en">Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.</title>
<author><name sortKey="Hauser, Robert A" sort="Hauser, Robert A" uniqKey="Hauser R" first="Robert A" last="Hauser">Robert A. Hauser</name>
<affiliation><nlm:affiliation>Department of Neurology, University of South Florida, Tampa, Florida 33606, USA. rhauser@health.usf.edu</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Shulman, Lisa M" sort="Shulman, Lisa M" uniqKey="Shulman L" first="Lisa M" last="Shulman">Lisa M. Shulman</name>
</author>
<author><name sortKey="Trugman, Joel M" sort="Trugman, Joel M" uniqKey="Trugman J" first="Joel M" last="Trugman">Joel M. Trugman</name>
</author>
<author><name sortKey="Roberts, John W" sort="Roberts, John W" uniqKey="Roberts J" first="John W" last="Roberts">John W. Roberts</name>
</author>
<author><name sortKey="Mori, Akihisa" sort="Mori, Akihisa" uniqKey="Mori A" first="Akihisa" last="Mori">Akihisa Mori</name>
</author>
<author><name sortKey="Ballerini, Rocco" sort="Ballerini, Rocco" uniqKey="Ballerini R" first="Rocco" last="Ballerini">Rocco Ballerini</name>
</author>
<author><name sortKey="Sussman, Neil M" sort="Sussman, Neil M" uniqKey="Sussman N" first="Neil M" last="Sussman">Neil M. Sussman</name>
</author>
</analytic>
<series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title>
<idno type="eISSN">1531-8257</idno>
<imprint><date when="2008" type="published">2008</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term>
<term>Analysis of Variance</term>
<term>Antiparkinson Agents (therapeutic use)</term>
<term>Double-Blind Method</term>
<term>Drug-Related Side Effects and Adverse Reactions</term>
<term>Dyskinesia, Drug-Induced (drug therapy)</term>
<term>Dyskinesia, Drug-Induced (etiology)</term>
<term>Female</term>
<term>Humans</term>
<term>Levodopa (adverse effects)</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Parkinson Disease (drug therapy)</term>
<term>Parkinson Disease (physiopathology)</term>
<term>Purines (therapeutic use)</term>
<term>Questionnaires</term>
<term>Severity of Illness Index</term>
<term>Time Factors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Levodopa</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antiparkinson Agents</term>
<term>Purines</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Dyskinesia, Drug-Induced</term>
<term>Parkinson Disease</term>
</keywords>
<keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term>
</keywords>
<keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Aged</term>
<term>Analysis of Variance</term>
<term>Double-Blind Method</term>
<term>Drug-Related Side Effects and Adverse Reactions</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Questionnaires</term>
<term>Severity of Illness Index</term>
<term>Time Factors</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.</div>
</front>
</TEI>
<pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">18831530</PMID>
<DateCreated><Year>2008</Year>
<Month>12</Month>
<Day>01</Day>
</DateCreated>
<DateCompleted><Year>2009</Year>
<Month>04</Month>
<Day>08</Day>
</DateCompleted>
<DateRevised><Year>2014</Year>
<Month>11</Month>
<Day>20</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1531-8257</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>23</Volume>
<Issue>15</Issue>
<PubDate><Year>2008</Year>
<Month>Nov</Month>
<Day>15</Day>
</PubDate>
</JournalIssue>
<Title>Movement disorders : official journal of the Movement Disorder Society</Title>
<ISOAbbreviation>Mov. Disord.</ISOAbbreviation>
</Journal>
<ArticleTitle>Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.</ArticleTitle>
<Pagination><MedlinePgn>2177-85</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1002/mds.22095</ELocationID>
<Abstract><AbstractText>The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hauser</LastName>
<ForeName>Robert A</ForeName>
<Initials>RA</Initials>
<AffiliationInfo><Affiliation>Department of Neurology, University of South Florida, Tampa, Florida 33606, USA. rhauser@health.usf.edu</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shulman</LastName>
<ForeName>Lisa M</ForeName>
<Initials>LM</Initials>
</Author>
<Author ValidYN="Y"><LastName>Trugman</LastName>
<ForeName>Joel M</ForeName>
<Initials>JM</Initials>
</Author>
<Author ValidYN="Y"><LastName>Roberts</LastName>
<ForeName>John W</ForeName>
<Initials>JW</Initials>
</Author>
<Author ValidYN="Y"><LastName>Mori</LastName>
<ForeName>Akihisa</ForeName>
<Initials>A</Initials>
</Author>
<Author ValidYN="Y"><LastName>Ballerini</LastName>
<ForeName>Rocco</ForeName>
<Initials>R</Initials>
</Author>
<Author ValidYN="Y"><LastName>Sussman</LastName>
<ForeName>Neil M</ForeName>
<Initials>NM</Initials>
</Author>
<Author ValidYN="Y"><CollectiveName>Istradefylline 6002-US-013 Study Group</CollectiveName>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D017428">Clinical Trial, Phase III</PublicationType>
<PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D016448">Multicenter Study</PublicationType>
<PublicationType UI="D016449">Randomized Controlled Trial</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Mov Disord</MedlineTA>
<NlmUniqueID>8610688</NlmUniqueID>
<ISSNLinking>0885-3185</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000978">Antiparkinson Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011687">Purines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>2GZ0LIK7T4</RegistryNumber>
<NameOfSubstance UI="C111599">istradefylline</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>46627O600J</RegistryNumber>
<NameOfSubstance UI="D007980">Levodopa</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000368">Aged</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D000704">Analysis of Variance</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D000978">Antiparkinson Agents</DescriptorName>
<QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D004311">Double-Blind Method</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D064420">Drug-Related Side Effects and Adverse Reactions</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D004409">Dyskinesia, Drug-Induced</DescriptorName>
<QualifierName MajorTopicYN="Y" UI="Q000188">drug therapy</QualifierName>
<QualifierName MajorTopicYN="N" UI="Q000209">etiology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D005260">Female</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D006801">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D007980">Levodopa</DescriptorName>
<QualifierName MajorTopicYN="N" UI="Q000009">adverse effects</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D008297">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D008875">Middle Aged</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D010300">Parkinson Disease</DescriptorName>
<QualifierName MajorTopicYN="N" UI="Q000188">drug therapy</QualifierName>
<QualifierName MajorTopicYN="N" UI="Q000503">physiopathology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D011687">Purines</DescriptorName>
<QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D011795">Questionnaires</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D012720">Severity of Illness Index</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName MajorTopicYN="N" UI="D013997">Time Factors</DescriptorName>
</MeshHeading>
</MeshHeadingList>
<InvestigatorList><Investigator ValidYN="Y"><LastName>Bodis-Wollner</LastName>
<ForeName>I</ForeName>
<Initials>I</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Calabrese</LastName>
<ForeName>V</ForeName>
<Initials>V</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Christine</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Colcher</LastName>
<ForeName>A</ForeName>
<Initials>A</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Elmer</LastName>
<ForeName>L</ForeName>
<Initials>L</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Evidente</LastName>
<ForeName>V</ForeName>
<Initials>V</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Harik</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hauser</LastName>
<ForeName>R</ForeName>
<Initials>R</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hermanowicz</LastName>
<ForeName>N</ForeName>
<Initials>N</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Hogarth</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Huang</LastName>
<ForeName>Z</ForeName>
<Initials>Z</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Krstevska</LastName>
<ForeName>S</ForeName>
<Initials>S</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Kurlan</LastName>
<ForeName>R</ForeName>
<Initials>R</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Novak</LastName>
<ForeName>P</ForeName>
<Initials>P</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Pahwa</LastName>
<ForeName>R</ForeName>
<Initials>R</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Roberts</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Seeberger</LastName>
<ForeName>L</ForeName>
<Initials>L</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Shannon</LastName>
<ForeName>K</ForeName>
<Initials>K</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Shulman</LastName>
<ForeName>L</ForeName>
<Initials>L</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Silver</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Simuni</LastName>
<ForeName>T</ForeName>
<Initials>T</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Sutton</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tarsy</LastName>
<ForeName>D</ForeName>
<Initials>D</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Tetrud</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Trugman</LastName>
<ForeName>J</ForeName>
<Initials>J</Initials>
</Investigator>
<Investigator ValidYN="Y"><LastName>Waters</LastName>
<ForeName>C</ForeName>
<Initials>C</Initials>
</Investigator>
</InvestigatorList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year>
<Month>10</Month>
<Day>4</Day>
<Hour>9</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2009</Year>
<Month>4</Month>
<Day>9</Day>
<Hour>9</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2008</Year>
<Month>10</Month>
<Day>4</Day>
<Hour>9</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="doi">10.1002/mds.22095</ArticleId>
<ArticleId IdType="pubmed">18831530</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Santé/explor/MovDisordV3/Data/PubMed/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001F96 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Corpus/biblio.hfd -nk 001F96 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Wicri/Santé |area= MovDisordV3 |flux= PubMed |étape= Corpus |type= RBID |clé= pubmed:18831530 |texte= Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Corpus/RBID.i -Sk "pubmed:18831530" \ | HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Corpus/biblio.hfd \ | NlmPubMed2Wicri -a MovDisordV3
![]() | This area was generated with Dilib version V0.6.23. | ![]() |