In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach
- Autores:
-
Maria I. Zapata-Cardona
Lizdany Florez-Alvarez
Ariadna L. Guerra-Sandoval
Mateo Chvatal-Medina
Carlos M. Guerra-Almonacid
Jaime Hincapie-Garcia
Juan C. Hernandez
Maria T. Rugeles
Wildeman Zapata-Builes
- Tipo de recurso:
- Article of journal
- Fecha de publicación:
- 2023
- Institución:
- Universidad Cooperativa de Colombia
- Repositorio:
- Repositorio UCC
- Idioma:
- eng
- OAI Identifier:
- oai:repository.ucc.edu.co:20.500.12494/57143
- Acceso en línea:
- https://hdl.handle.net/20.500.12494/57143
- Palabra clave:
- antiretrovirals
SARS-CoV-2
COVID-19
molecular docking
drug repurposing
- Rights
- openAccess
- License
- http://creativecommons.org/publicdomain/zero/1.0/
id |
COOPER2_cdc646def5b5d99aaeb8d602e4b4eff9 |
---|---|
oai_identifier_str |
oai:repository.ucc.edu.co:20.500.12494/57143 |
network_acronym_str |
COOPER2 |
network_name_str |
Repositorio UCC |
repository_id_str |
|
dc.title.none.fl_str_mv |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
title |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
spellingShingle |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach antiretrovirals SARS-CoV-2 COVID-19 molecular docking drug repurposing |
title_short |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
title_full |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
title_fullStr |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
title_full_unstemmed |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
title_sort |
In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach |
dc.creator.fl_str_mv |
Maria I. Zapata-Cardona Lizdany Florez-Alvarez Ariadna L. Guerra-Sandoval Mateo Chvatal-Medina Carlos M. Guerra-Almonacid Jaime Hincapie-Garcia Juan C. Hernandez Maria T. Rugeles Wildeman Zapata-Builes |
dc.contributor.author.none.fl_str_mv |
Maria I. Zapata-Cardona Lizdany Florez-Alvarez Ariadna L. Guerra-Sandoval Mateo Chvatal-Medina Carlos M. Guerra-Almonacid Jaime Hincapie-Garcia Juan C. Hernandez Maria T. Rugeles Wildeman Zapata-Builes |
dc.contributor.researchgroup.none.fl_str_mv |
INFETTARE |
dc.subject.proposal.none.fl_str_mv |
antiretrovirals SARS-CoV-2 COVID-19 molecular docking drug repurposing |
topic |
antiretrovirals SARS-CoV-2 COVID-19 molecular docking drug repurposing |
publishDate |
2023 |
dc.date.issued.none.fl_str_mv |
2023-01-16 |
dc.date.accessioned.none.fl_str_mv |
2024-09-27T02:57:31Z |
dc.date.available.none.fl_str_mv |
2024-09-27T02:57:31Z |
dc.type.none.fl_str_mv |
Artículo de revista |
dc.type.coar.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
dc.type.coar.none.fl_str_mv |
http://purl.org/coar/resource_type/c_6501 |
dc.type.coarversion.none.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
dc.type.content.none.fl_str_mv |
Text |
dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.redcol.none.fl_str_mv |
http://purl.org/redcol/resource_type/ART |
dc.type.version.none.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
http://purl.org/coar/resource_type/c_6501 |
status_str |
publishedVersion |
dc.identifier.citation.none.fl_str_mv |
Maria I. Zapata-Cardona, Lizdany Florez-Alvarez, Ariadna L. Guerra-Sandoval, Mateo Chvatal-Medina, Carlos M. Guerra-Almonacid, Jaime Hincapie-Garcia, Juan C. Hernandez, Maria T. Rugeles, Wildeman Zapata-Builes. In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach[J]. AIMS Microbiology, 2023, 9(1): 20-40. doi: 10.3934/microbiol.2023002 |
dc.identifier.issn.none.fl_str_mv |
2471-1888 |
dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/20.500.12494/57143 |
dc.identifier.doi.none.fl_str_mv |
10.3934/microbiol.2023002 |
dc.identifier.eissn.none.fl_str_mv |
2471-1888 |
identifier_str_mv |
Maria I. Zapata-Cardona, Lizdany Florez-Alvarez, Ariadna L. Guerra-Sandoval, Mateo Chvatal-Medina, Carlos M. Guerra-Almonacid, Jaime Hincapie-Garcia, Juan C. Hernandez, Maria T. Rugeles, Wildeman Zapata-Builes. In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach[J]. AIMS Microbiology, 2023, 9(1): 20-40. doi: 10.3934/microbiol.2023002 2471-1888 10.3934/microbiol.2023002 |
url |
https://hdl.handle.net/20.500.12494/57143 |
dc.language.iso.none.fl_str_mv |
eng |
language |
eng |
dc.relation.citationendpage.none.fl_str_mv |
40 |
dc.relation.citationissue.none.fl_str_mv |
1 |
dc.relation.citationstartpage.none.fl_str_mv |
20 |
dc.relation.citationvolume.none.fl_str_mv |
9 |
dc.relation.ispartofjournal.none.fl_str_mv |
AIMS Microbiology |
dc.relation.references.none.fl_str_mv |
1. W.H.O., WHO Director-General’ opening remarks at the media briefing on COVID-19-11 March 2020, 2020. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. 2. Lopera TJ, Chvatal-Medina M, Florez-Alvarez L, et al. (2022) Humoral response to BNT162b2 vaccine against SARS-CoV-2 variants decays after six months. Front Immunol 13: 879036. https://doi.org/10.3389/fimmu.2022.879036 3. Tada T, Zhou H, Dcosta BM, et al. (2021) Partial resistance of SARS-CoV-2 Delta variants to vaccine-elicited antibodies and convalescent sera. iScience 24: 103341. https://doi.org/10.1016/j.isci.2021.103341 4. Hoffmann M, Kruger N, Schulz S, et al. (2022) The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic. Cell 185: 447–456. https://doi.org/10.1016/j.cell.2021.12.032 5. Wang MY, Zhao R, Gao LJ, et al. (2020) SARS-CoV-2: structure, biology, and structure-based therapeutics development. Front Cell Infect Microbiol 10: 587269. https://doi.org/10.3389/fcimb.2020.587269 6. Yadav R, Chaudhary JK, Jain N, et al. (2021) Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells 10: 821. https://doi.org/10.3390/cells10040821 7. Yang H and Rao Z (2021) Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol 19: 685–700. https://doi.org/10.1038/s41579-021-00630-8 8. Gao Y, Yan L, Huang Y, et al. (2020) Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 368: 779–782. https://doi.org/10.1126/science.abb7498 9. Lin S, Chen H, Chen Z, et al. (2021) Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity. Nucleic Acids Res 49: 5382–5392. https://doi.org/10.1093/nar/gkab320 10. Baddock H, Brolih S, Yosaatmadja Y, et al. (2022) Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification. Nucleic Acids Res 50: 1484–1500. https://doi.org/10.1093/nar/gkab1303 11. V’kovski P, Kratzel A, Steiner S, et al. (2021) Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 19: 155–170. https://doi.org/10.1038/s41579-020-00468-6 12. Mosquera-Yuqui F, Lopez-Guerra N, Moncayo-Palacio EA (2020) Targeting the 3CLpro and RdRp of SARS-CoV-2 with phytochemicals from medicinal plants of the Andean Region: molecular docking and molecular dynamics simulations. J Biomol Struct Dyn 40: 2010–2023. https://doi.org/10.1080/07391102.2020.1835716 13. Peele KA, Potla Durthi C, Srihansa T, et al. (2020) Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study. Inform Med Unlocked 19: 100345. https://doi.org/10.1016/j.imu.2020.100345 14. Cao B, Wang Y, Wen D, et al. (2020) A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382: 1787–1799. https://doi.org/10.1056/NEJMoa2001282 15. Arabi YM, Gordon AC, Derde LPG, et al. (2021) Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Med 47: 867–886. https://doi.org/10.1007/s00134-021-06448-5 16. Beck BR, Shin B, Choi Y, et al. (2020) Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model. Comput Struct Biotechnol J 18: 784–790. https://doi.org/10.1016/j.csbj.2020.03.025 17. Jordaan MA, Ebenezer O, Damoyi N, et al. (2020) Virtual screening, molecular docking studies and DFT calculations of FDA approved compounds similar to the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Heliyon 6: e04642. https://doi.org/10.1016/j.heliyon.2020.e04642 18. Indu P, Rameshkumar MR, Arunagirinathan N, et al. (2020) Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNA-dependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach. J Infect Public Health 13: 1856–1861. https://doi.org/10.1016/j.jiph.2020.10.015 19. Jockusch S, Tao C, Li X, et al. (2020) Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase. bioRxiv: 2020. https://doi.org/10.1101/2020.04.03.022939 20. Alavian G, Kolahdouzan K, Mortezazadeh M, et al. (2021) Antiretrovirals for Prophylaxis Against COVID-19: A Comprehensive Literature Review. J Clin Pharmacol 61: 581–590. https://doi.org/10.1002/jcph.1788 |
dc.rights.uri.none.fl_str_mv |
http://creativecommons.org/publicdomain/zero/1.0/ |
dc.rights.accessrights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
dc.rights.creativecommons.en.fl_str_mv |
CC0 1.0 Universal |
dc.rights.coar.none.fl_str_mv |
http://purl.org/coar/access_right/c_abf2 |
rights_invalid_str_mv |
http://creativecommons.org/publicdomain/zero/1.0/ CC0 1.0 Universal http://purl.org/coar/access_right/c_abf2 |
eu_rights_str_mv |
openAccess |
dc.format.extent.none.fl_str_mv |
1-21 |
dc.format.mimetype.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Grupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia. |
dc.publisher.place.none.fl_str_mv |
Externo |
publisher.none.fl_str_mv |
Grupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia. |
dc.source.none.fl_str_mv |
https://www.aimspress.com/article/doi/10.3934/microbiol.2023002 |
institution |
Universidad Cooperativa de Colombia |
bitstream.url.fl_str_mv |
https://repository.ucc.edu.co/bitstreams/49cad309-dfbd-44f6-9ec2-d9812175a6df/download https://repository.ucc.edu.co/bitstreams/32e76d32-5936-448a-a559-22109ab84f0d/download https://repository.ucc.edu.co/bitstreams/460605e0-af79-45a8-8c63-ae3154df0612/download https://repository.ucc.edu.co/bitstreams/64809d23-1b9f-41ab-ba12-435c8b312796/download https://repository.ucc.edu.co/bitstreams/f5d7c6e7-deed-4398-9ee9-6a8704a705b9/download |
bitstream.checksum.fl_str_mv |
3bce4f7ab09dfc588f126e1e36e98a45 42fd4ad1e89814f5e4a476b409eb708c ef26da7331dc88e7fc5cd50fc6e44d3a 67ee058ec66e8fdff1fca85f9a5ff301 da0777488914b08d45b20edad75f5999 |
bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 MD5 MD5 |
repository.name.fl_str_mv |
Repositorio Institucional Universidad Cooperativa de Colombia |
repository.mail.fl_str_mv |
bdigital@metabiblioteca.com |
_version_ |
1814247112911618048 |
spelling |
Maria I. Zapata-CardonaLizdany Florez-AlvarezAriadna L. Guerra-SandovalMateo Chvatal-MedinaCarlos M. Guerra-AlmonacidJaime Hincapie-GarciaJuan C. HernandezMaria T. RugelesWildeman Zapata-BuilesINFETTARE2024-09-27T02:57:31Z2024-09-27T02:57:31Z2023-01-16Maria I. Zapata-Cardona, Lizdany Florez-Alvarez, Ariadna L. Guerra-Sandoval, Mateo Chvatal-Medina, Carlos M. Guerra-Almonacid, Jaime Hincapie-Garcia, Juan C. Hernandez, Maria T. Rugeles, Wildeman Zapata-Builes. In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approach[J]. AIMS Microbiology, 2023, 9(1): 20-40. doi: 10.3934/microbiol.20230022471-1888https://hdl.handle.net/20.500.12494/5714310.3934/microbiol.20230022471-18881-21application/pdfengGrupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia.Externohttp://creativecommons.org/publicdomain/zero/1.0/info:eu-repo/semantics/openAccessCC0 1.0 Universalhttp://purl.org/coar/access_right/c_abf2https://www.aimspress.com/article/doi/10.3934/microbiol.2023002In vitro and in silico evaluation of antiretrovirals against SARS-CoV-2: A drug repurposing approachArtículo de revistahttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/coar/version/c_970fb48d4fbd8a85Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/publishedVersion401209AIMS Microbiology1. W.H.O., WHO Director-General’ opening remarks at the media briefing on COVID-19-11 March 2020, 2020. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020.2. Lopera TJ, Chvatal-Medina M, Florez-Alvarez L, et al. (2022) Humoral response to BNT162b2 vaccine against SARS-CoV-2 variants decays after six months. Front Immunol 13: 879036. https://doi.org/10.3389/fimmu.2022.8790363. Tada T, Zhou H, Dcosta BM, et al. (2021) Partial resistance of SARS-CoV-2 Delta variants to vaccine-elicited antibodies and convalescent sera. iScience 24: 103341. https://doi.org/10.1016/j.isci.2021.1033414. Hoffmann M, Kruger N, Schulz S, et al. (2022) The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic. Cell 185: 447–456. https://doi.org/10.1016/j.cell.2021.12.0325. Wang MY, Zhao R, Gao LJ, et al. (2020) SARS-CoV-2: structure, biology, and structure-based therapeutics development. Front Cell Infect Microbiol 10: 587269. https://doi.org/10.3389/fcimb.2020.5872696. Yadav R, Chaudhary JK, Jain N, et al. (2021) Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells 10: 821. https://doi.org/10.3390/cells100408217. Yang H and Rao Z (2021) Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol 19: 685–700. https://doi.org/10.1038/s41579-021-00630-88. Gao Y, Yan L, Huang Y, et al. (2020) Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 368: 779–782. https://doi.org/10.1126/science.abb74989. Lin S, Chen H, Chen Z, et al. (2021) Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity. Nucleic Acids Res 49: 5382–5392. https://doi.org/10.1093/nar/gkab32010. Baddock H, Brolih S, Yosaatmadja Y, et al. (2022) Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification. Nucleic Acids Res 50: 1484–1500. https://doi.org/10.1093/nar/gkab130311. V’kovski P, Kratzel A, Steiner S, et al. (2021) Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 19: 155–170. https://doi.org/10.1038/s41579-020-00468-612. Mosquera-Yuqui F, Lopez-Guerra N, Moncayo-Palacio EA (2020) Targeting the 3CLpro and RdRp of SARS-CoV-2 with phytochemicals from medicinal plants of the Andean Region: molecular docking and molecular dynamics simulations. J Biomol Struct Dyn 40: 2010–2023. https://doi.org/10.1080/07391102.2020.183571613. Peele KA, Potla Durthi C, Srihansa T, et al. (2020) Molecular docking and dynamic simulations for antiviral compounds against SARS-CoV-2: A computational study. Inform Med Unlocked 19: 100345. https://doi.org/10.1016/j.imu.2020.10034514. Cao B, Wang Y, Wen D, et al. (2020) A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 382: 1787–1799. https://doi.org/10.1056/NEJMoa200128215. Arabi YM, Gordon AC, Derde LPG, et al. (2021) Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Intensive Care Med 47: 867–886. https://doi.org/10.1007/s00134-021-06448-516. Beck BR, Shin B, Choi Y, et al. (2020) Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model. Comput Struct Biotechnol J 18: 784–790. https://doi.org/10.1016/j.csbj.2020.03.02517. Jordaan MA, Ebenezer O, Damoyi N, et al. (2020) Virtual screening, molecular docking studies and DFT calculations of FDA approved compounds similar to the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Heliyon 6: e04642. https://doi.org/10.1016/j.heliyon.2020.e0464218. Indu P, Rameshkumar MR, Arunagirinathan N, et al. (2020) Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNA-dependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach. J Infect Public Health 13: 1856–1861. https://doi.org/10.1016/j.jiph.2020.10.01519. Jockusch S, Tao C, Li X, et al. (2020) Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase. bioRxiv: 2020. https://doi.org/10.1101/2020.04.03.02293920. Alavian G, Kolahdouzan K, Mortezazadeh M, et al. (2021) Antiretrovirals for Prophylaxis Against COVID-19: A Comprehensive Literature Review. J Clin Pharmacol 61: 581–590. https://doi.org/10.1002/jcph.1788antiretroviralsSARS-CoV-2COVID-19molecular dockingdrug repurposingPublicationLICENSElicense.txtlicense.txttext/plain; charset=utf-84334https://repository.ucc.edu.co/bitstreams/49cad309-dfbd-44f6-9ec2-d9812175a6df/download3bce4f7ab09dfc588f126e1e36e98a45MD52CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8701https://repository.ucc.edu.co/bitstreams/32e76d32-5936-448a-a559-22109ab84f0d/download42fd4ad1e89814f5e4a476b409eb708cMD53ORIGINALAntiretrovirals and COVID19 UCC_UdeA 2023.pdfAntiretrovirals and COVID19 UCC_UdeA 2023.pdfapplication/pdf619109https://repository.ucc.edu.co/bitstreams/460605e0-af79-45a8-8c63-ae3154df0612/downloadef26da7331dc88e7fc5cd50fc6e44d3aMD54TEXTAntiretrovirals and COVID19 UCC_UdeA 2023.pdf.txtAntiretrovirals and COVID19 UCC_UdeA 2023.pdf.txtExtracted texttext/plain63003https://repository.ucc.edu.co/bitstreams/64809d23-1b9f-41ab-ba12-435c8b312796/download67ee058ec66e8fdff1fca85f9a5ff301MD55THUMBNAILAntiretrovirals and COVID19 UCC_UdeA 2023.pdf.jpgAntiretrovirals and COVID19 UCC_UdeA 2023.pdf.jpgGenerated Thumbnailimage/jpeg15485https://repository.ucc.edu.co/bitstreams/f5d7c6e7-deed-4398-9ee9-6a8704a705b9/downloadda0777488914b08d45b20edad75f5999MD5620.500.12494/57143oai:repository.ucc.edu.co:20.500.12494/571432024-09-27 03:07:56.489http://creativecommons.org/publicdomain/zero/1.0/CC0 1.0 Universalopen.accesshttps://repository.ucc.edu.coRepositorio Institucional Universidad Cooperativa de Colombiabdigital@metabiblioteca.comVU5JVkVSU0lEQUQgQ09PUEVSQVRJVkEgREUgQ09MT01CSUEKUkVQT1NJVE9SSU9TIElOU1RJVFVDSU9OQUxFUwpMSUNFTkNJQSBERSBVU08KClBvciBtZWRpbyBkZWwgcHJlc2VudGUgZG9jdW1lbnRvLCBlbCBBdXRvcihlcyksIG1heW9yIChlcykgZGUgZWRhZCwgcXVpZW4gZW4gYWRlbGFudGUgc2UgZGVub21pbmFyw6EgZWwgQVVUT1IsIGNvbmZpZXJlIGEgbGEgVU5JVkVSU0lEQUQgQ09PUEVSQVRJVkEgREUgQ09MT01CSUEsIGNvbiBOSVQuIDg2MC0wMjk5MjQtNywgdW5hIExJQ0VOQ0lBIERFIFVTTyBkZSBvYnJhLCBiYWpvIGxhcyBzaWd1aWVudGVzIGNvbmRpY2lvbmVzLgoKQ0zDgVVTVUxBUwoKUFJJTUVSQS4gT2JqZXRvLiBFTCBBVVRPUiBwb3IgZXN0ZSBhY3RvIGF1dG9yaXphIGxhIHV0aWxpemFjacOzbiBkZSBsYSBvYnJhLCBkZSBjb25mb3JtaWRhZCBjb24gbG8gZXN0aXB1bGFkbyBhIGNvbnRpbnVhY2nDs246IAoKKGEpIFBhcmEgZWZlY3RvcyBkZSBsYSBwcmVzZW50ZSBsaWNlbmNpYSBzZSBhdXRvcml6YSBsYSByZXByb2R1Y2Npw7NuIGRlIGxhIG9icmEgYW50ZXJpb3JtZW50ZSBjaXRhZGEsIGxhIGN1YWwgc2UgYWxvamFyw6EgZW4gZm9ybWF0byBkaWdpdGFsIGVuIGxhcyBwbGF0YWZvcm1hcyBvIHJlcG9zaXRvcmlvcyBhZG1pbmlzdHJhZG9zIHBvciBsYSBVTklWRVJTSURBRCBvIGVuIG90cm8gdGlwbyBkZSByZXBvc2l0b3Jpb3MgZXh0ZXJub3MgbyBww6FnaW5hcyB3ZWIgZXNjb2dpZG9zIHBvciBsYSBVTklWRVJTSURBRCwgcGFyYSBmaW5lcyBkZSBkaWZ1c2nDs24geSBkaXZ1bGdhY2nDs24uIEFkaWNpb25hbG1lbnRlLCBzZSBhdXRvcml6YSBhIHF1ZSBsb3MgdXN1YXJpb3MgaW50ZXJub3MgeSBleHRlcm5vcyBkZSBkaWNoYXMgcGxhdGFmb3JtYXMgbyByZXBvc2l0b3Jpb3MgcmVwcm9kdXpjYW4gbyBkZXNjYXJndWVuIGxhIG9icmEsIHNpbiDDoW5pbW8gZGUgbHVjcm8sIHBhcmEgZmluZXMgcHJpdmFkb3MsIGVkdWNhdGl2b3MgbyBhY2Fkw6ltaWNvczsgc2llbXByZSB5IGN1YW5kbyBubyBzZSB2aW9sZW4gYWN1ZXJkb3MgY29uIGVkaXRvcmVzLCBwZXJpb2RvcyBkZSBlbWJhcmdvIG8gYWN1ZXJkb3MgZGUgY29uZmlkZW5jaWFsaWRhZCBxdWUgYXBsaXF1ZW4uCgooYikgU2UgYXV0b3JpemEgbGEgY29tdW5pY2FjacOzbiBww7pibGljYSB5IGxhIHB1ZXN0YSBhIGRpc3Bvc2ljacOzbiBkZSBsYSBvYnJhIG1lbmNpb25hZGEsIGVuIGFjY2VzbyBhYmllcnRvLCBwYXJhIHN1IHV0aWxpemFjacOzbiBlbiBsYXMgcGxhdGFmb3JtYXMgbyByZXBvc2l0b3Jpb3MgYWRtaW5pc3RyYWRvcyBwb3IgbGEgVU5JVkVSU0lEQUQuCgooYykgTG8gYW50ZXJpb3IgZXN0YXLDoSBzdWpldG8gYSBsYXMgZGVmaW5pY2lvbmVzIGNvbnRlbmlkYXMgZW4gbGEgRGVjaXNpw7NuIEFuZGluYSAzNTEgZGUgMTk5MyB5IGxhIExleSAyMyBkZSAxOTgyLgoKClNFR1VOREEuIE9yaWdpbmFsaWRhZCB5IHJlY2xhbWFjaW9uZXMuIEVsIEFVVE9SIGRlY2xhcmEgcXVlIGxhIE9CUkEgZXMgb3JpZ2luYWwgeSBxdWUgZXMgZGUgc3UgY3JlYWNpw7NuIGV4Y2x1c2l2YSwgbm8gZXhpc3RpZW5kbyBpbXBlZGltZW50byBkZSBjdWFscXVpZXIgbmF0dXJhbGV6YSAoZW1iYXJnb3MsIHVzbyBkZSBtYXRlcmlhbCBwcm90ZWdpZG8gcG9yIGRlcmVjaG9zIGRlIGF1dG9yKSBwYXJhIGxhIGNvbmNlc2nDs24gZGUgbG9zIGRlcmVjaG9zIHByZXZpc3RvcyBlbiBlc3RlIGFjdWVyZG8uIEVsIEFVVE9SIHJlc3BvbmRlcsOhIHBvciBjdWFscXVpZXIgYWNjacOzbiBkZSByZWl2aW5kaWNhY2nDs24sIHBsYWdpbyB1IG90cmEgY2xhc2UgZGUgcmVjbGFtYWNpw7NuIHF1ZSBhbCByZXNwZWN0byBwdWRpZXJhIHNvYnJldmVuaXIuCgpURVJDRVJBLiBDb250cmFwcmVzdGFjacOzbi4gRWwgQVVUT1IgYXV0b3JpemEgYSBxdWUgc3Ugb2JyYSBzZWEgdXRpbGl6YWRhIGRlIGNvbmZvcm1pZGFkIGNvbiBsYSBjbMOhdXN1bGEgUFJJTUVSQSBkZSBmb3JtYSBncmF0dWl0YSwgZXMgZGVjaXIsIHF1ZSBsYSB1dGlsaXphY2nDs24gZGUgbGEgbWlzbWEgbm8gZ2VuZXJhIG5pbmfDum4gcGFnbyBvIHJlZ2Fsw61hcyBlbiBmYXZvciBkZSBlc3RlLgoKQ1VBUlRBLiBUaXR1bGFyaWRhZCBkZSBkZXJlY2hvcy4gRWwgcHJlc2VudGUgY29udHJhdG8gbm8gdHJhbnNmaWVyZSBsYSB0aXR1bGFyaWRhZCBkZSBsb3MgZGVyZWNob3MgcGF0cmltb25pYWxlcyBzb2JyZSBsYXMgb2JyYXMgYW50ZXJpb3JtZW50ZSBtZW5jaW9uYWRhcyBhIGxhIFVOSVZFUlNJREFELiDDmm5pY2FtZW50ZSBoYWNlIHJlbGFjacOzbiBhIHVuYSBsaWNlbmNpYSBubyBleGNsdXNpdmEgZW4gbG9zIHTDqXJtaW5vcyB5IGNvbmRpY2lvbmVzIGFudGVyaW9ybWVudGUgcGFjdGFkb3MuCgpRVUlOVEEuIENyw6lkaXRvcy4gTGEgVU5JVkVSU0lEQUQgc2UgY29tcHJvbWV0ZSBhIGRhciBhbCBBVVRPUiwgZWwgcmVjb25vY2ltaWVudG8gZGVudHJvIGNhZGEgZm9ybWEgZGUgdXRpbGl6YWNpw7NuIGVuIGxhIG9icmEuIExvcyBjcsOpZGl0b3MgZGViZW4gZmlndXJhciBlbiBjYWRhIHVubyBkZSBsb3MgZm9ybWF0b3MgbyByZWdpc3Ryb3MgZGUgcHVibGljYWNpw7NuLiBObyBjb25zdGl0dWlyw6EgdW5hIHZpb2xhY2nDs24gYSBsb3MgZGVyZWNob3MgbW9yYWxlcyBkZWwgYXV0b3IgbGEgbm8gcmVwcm9kdWNjacOzbiwgY29tdW5pY2FjacOzbiBvIGRlbcOhcyB1dGlsaXphY2lvbmVzIGRlIGxhIG9icmEuIExhIHV0aWxpemFjacOzbiBvIG5vIGRlIGxhIG9icmEsIGFzw60gY29tbyBzdSBmb3JtYSBkZSB1dGlsaXphY2nDs24gc2Vyw6EgZmFjdWx0YWQgZXhjbHVzaXZhIGRlIGxhIFVOSVZFUlNJREFELgogClNFWFRBLiBEdXJhY2nDs24geSB0ZXJyaXRvcmlvLiBMYSBwcmVzZW50ZSBsaWNlbmNpYSBkZSB1c28gcXVlIHNlIG90b3JnYSBhIGZhdm9yIGRlIGxhIFVOSVZFUlNJREFEIHRlbmRyw6EgdW5hIGR1cmFjacOzbiBlcXVpdmFsZW50ZSBhbCB0w6lybWlubyBkZSBwcm90ZWNjacOzbiBsZWdhbCBkZSBsYSBvYnJhIHkgcGFyYSB0b2RvcyBsb3MgcGHDrXNlcyBkZWwgbXVuZG8uCgpTw4lQVElNQS4gVXNvIGRlIENyZWF0aXZlIENvbW1vbnMuIEVsIEFVVE9SIGF1dG9yaXphcsOhIGxhIGRpZnVzacOzbiBkZSBzdSBjb250ZW5pZG8gYmFqbyB1bmEgbGljZW5jaWEgQ3JlYXRpdmUgQ29tbW9ucyBhdHJpYnVjacOzbiA0LjAgaW50ZXJuYWNpb25hbCwgcXVlIGRlYmVyw6EgaW5jbHVpcnNlIGVuIGVsIGNvbnRlbmlkby4gCgpPQ1RBVkEuIERlcmVjaG8gZGUgZXhjbHVzacOzbi4gQ2FkYSBhdXRvciBwdWVkZSBpbmRpY2FyIGVuIGVsIG1vbWVudG8gZGUgZGVww7NzaXRvIGRlbCBjb250ZW5pZG8gcXVlIGVsIHRleHRvIGNvbXBsZXRvIGRlIGxhIHByb2R1Y2Npw7NuIGFjYWTDqW1pY2EgbyBjaWVudMOtZmljYSBubyBlc3RlIGNvbiBhY2Nlc28gYWJpZXJ0byBlbiBlbCBSZXBvc2l0b3JpbyBJbnN0aXR1Y2lvbmFsIHBvciBtb3Rpdm9zIGRlIGNvbmZpZGVuY2lhbGlkYWQsIHBvcnF1ZSBzZSBlbmN1ZW50cmUgZW4gdsOtYXMgZGUgb2J0ZW5lciB1biBkZXJlY2hvIGRlIHByb3BpZWRhZCBpbmR1c3RyaWFsIG8gZXhpc3RpciBhY3VlcmRvcyBwcmV2aW9zIGNvbiB0ZXJjZXJvcyAoZWRpdG9yaWFsZXMsIHJldmlzdGFzIGNpZW50w61maWNhcywgb3RyYXMgaW5zdGl0dWNpb25lcykuIEVsIGF1dG9yIHNlIGNvbXByb21ldGUgYSBkZXBvc2l0YXIgbG9zIG1ldGFkYXRvcyBlIGluZm9ybWFyIGVsIHRpZW1wbyBkZSBlbWJhcmdvIGR1cmFudGUgZWwgY3VhbCBlbCB0ZXh0byBjb21wbGV0byB0ZW5kcsOhIGFjY2VzbyByZXN0cmluZ2lkby4gCgpOT1ZFTkEuIEVsIEFVVE9SIGFsIGFjZXB0YXIgZXN0YSBsaWNlbmNpYSBhZHVjZSBxdWUgZXN0YSBwcm9kdWNjacOzbiBzZSBkZXNhcnJvbGzDsyBlbiBlbCBwZXJpb2RvIGVuIHF1ZSBzZSBlbmN1ZW50cmEgY29uIHbDrW5jdWxvcyBjb24gTGEgVW5pdmVyc2lkYWQuCgpEw4lDSU1BLiBOb3JtYXMgYXBsaWNhYmxlcy4gUGFyYSBsYSBpbnRlcnByZXRhY2nDs24geSBjdW1wbGltaWVudG8gZGVsIHByZXNlbnRlIGFjdWVyZG8gbGFzIHBhcnRlcyBzZSBzb21ldGVuIGEgbGEgRGVjaXNpw7NuIEFuZGluYSAzNTEgZGUgMTk5MywgbGEgTGV5IDIzIGRlIDE5ODIgeSBkZW3DoXMgbm9ybWFzIGFwbGljYWJsZXMgZGUgQ29sb21iaWEuIEFkZW3DoXMsIGEgbGFzIG5vcm1hcyBJbnN0aXR1Y2lvbmFsZXMgcXVlIGFwbGlxdWVuLgoKTGEgcHJlc2VudGUgbGljZW5jaWEgc2UgYXV0b3JpemEgZW4gbGEgZmVjaGEgZGUgcHVibGljYWNpw7NuIGVuIGxvcyByZXBvc2l0b3Jpb3MgaW5zdGl0dWNpb25hbGVzLgo= |