메뉴 건너뛰기




Volumn 50, Issue 1, 2016, Pages 39-46

Daclatasvir: A NS5A replication complex inhibitor for hepatitis C infection

Author keywords

BMS 790052; Daclatasvir; Hepatitis C; NS5A inhibitor

Indexed keywords

ABACAVIR; ASUNAPREVIR; BECLABUVIR; DACLATASVIR; DARUNAVIR PLUS RITONAVIR; DOLUTEGRAVIR; EMTRICITABINE; ENFUVIRTIDE; LAMIVUDINE; LOPINAVIR PLUS RITONAVIR; MARAVIROC; PEGINTERFERON; RALTEGRAVIR; RIBAVIRIN; RILPIVIRINE; SOFOSBUVIR; TENOFOVIR; TRIACYLGLYCEROL LIPASE; ZIDOVUDINE; ANTIVIRUS AGENT; BMS-790052; IMIDAZOLE DERIVATIVE; NS-5 PROTEIN, HEPATITIS C VIRUS; VIRAL PROTEIN;

EID: 84981541178     PISSN: 10600280     EISSN: 15426270     Source Type: Journal    
DOI: 10.1177/1060028015610342     Document Type: Review
Times cited : (52)

References (42)
  • 1
    • 84867288022 scopus 로고    scopus 로고
    • Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965
    • Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.
    • (2012) MMWR Recomm Rep , vol.61 , Issue.RR-4 , pp. 1-32
  • 2
    • 84881637752 scopus 로고    scopus 로고
    • Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement
    • Moyer VA. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159:349-357.
    • (2013) Ann Intern Med , vol.159 , pp. 349-357
    • Moyer, V.A.1
  • 3
    • 80053339008 scopus 로고    scopus 로고
    • An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases
    • Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444.
    • (2011) Hepatology , vol.54 , pp. 1433-1444
    • Ghany, M.G.1    Nelson, D.R.2    Strader, D.B.3    Thomas, D.L.4    Seeff, L.B.5
  • 4
    • 84892761609 scopus 로고    scopus 로고
    • Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection
    • Everson GT, Sims KD, Rodriguez-Torres M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014;146:420-429.
    • (2014) Gastroenterology , vol.146 , pp. 420-429
    • Everson, G.T.1    Sims, K.D.2    Rodriguez-Torres, M.3
  • 5
    • 84939265322 scopus 로고    scopus 로고
    • Princeton, NJ: Bristol- Meyers Squibb Company
    • Daklinza [prescribing information]. Princeton, NJ: Bristol- Meyers Squibb Company; 2015.
    • (2015) Daklinza [Prescribing Information]
  • 6
    • 84904507580 scopus 로고    scopus 로고
    • Sofosbuvir: A nucleotide NS5B inhibitor for the treatment of chronic hepatitis C infection
    • Rose L, Bias TE, Mathias CB, Trooskin SB, Fong JJ. Sofosbuvir: a nucleotide NS5B inhibitor for the treatment of chronic hepatitis C infection. Ann Pharmacother. 2014;48:1019-1029.
    • (2014) Ann Pharmacother , vol.48 , pp. 1019-1029
    • Rose, L.1    Bias, T.E.2    Mathias, C.B.3    Trooskin, S.B.4    Fong, J.J.5
  • 7
    • 84896308812 scopus 로고    scopus 로고
    • Discovery and development of hepatitis C virus NS5A replication complex inhibitors
    • Belema M, Lopez OD, Bender JA, et al. Discovery and development of hepatitis C virus NS5A replication complex inhibitors. J Med Chem. 2014;57:1643-1672.
    • (2014) J Med Chem , vol.57 , pp. 1643-1672
    • Belema, M.1    Lopez, O.D.2    Bender, J.A.3
  • 8
    • 79955532870 scopus 로고    scopus 로고
    • The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein
    • Lee C, Ma H, Hang JQ, et al. The hepatitis C virus NS5A inhibitor (BMS-790052) alters the subcellular localization of the NS5A non-structural viral protein. Virology. 2011;414:10-18.
    • (2011) Virology , vol.414 , pp. 10-18
    • Lee, C.1    Ma, H.2    Hang, J.Q.3
  • 9
    • 84921317221 scopus 로고    scopus 로고
    • Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides
    • Chukkapalli V, Berger KL, Kelly SM, Thomas M, Deiters A, Randall G. Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides. Virology. 2015;476:168-179.
    • (2015) Virology , vol.476 , pp. 168-179
    • Chukkapalli, V.1    Berger, K.L.2    Kelly, S.M.3    Thomas, M.4    Deiters, A.5    Randall, G.6
  • 10
    • 84918549836 scopus 로고    scopus 로고
    • Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition
    • Nettles JH, Stanton RA, Broyde J, et al. Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition. J Med Chem. 2014;57:10031-10043.
    • (2014) J Med Chem , vol.57 , pp. 10031-10043
    • Nettles, J.H.1    Stanton, R.A.2    Broyde, J.3
  • 11
    • 84874644131 scopus 로고    scopus 로고
    • Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life
    • Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci U S A. 2013;110:3991-3996.
    • (2013) Proc Natl Acad Sci U S A , vol.110 , pp. 3991-3996
    • Guedj, J.1    Dahari, H.2    Rong, L.3
  • 12
    • 82455192239 scopus 로고    scopus 로고
    • Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: In vitro and in vivo correlations
    • Fridell RA, Wang C, Sun JH, et al. Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in humans: in vitro and in vivo correlations. Hepatology. 2011;54:1924-1935.
    • (2011) Hepatology , vol.54 , pp. 1924-1935
    • Fridell, R.A.1    Wang, C.2    Sun, J.H.3
  • 13
    • 77956116880 scopus 로고    scopus 로고
    • Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system
    • Fridell RA, Qiu D, Wang C, Valera L, Gao M. Resistance analysis of the hepatitis C virus NS5A inhibitor BMS-790052 in an in vitro replicon system. Antimicrob Agents Chemother. 2010;54:3641-3650.
    • (2010) Antimicrob Agents Chemother , vol.54 , pp. 3641-3650
    • Fridell, R.A.1    Qiu, D.2    Wang, C.3    Valera, L.4    Gao, M.5
  • 14
    • 82455188181 scopus 로고    scopus 로고
    • Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1
    • Nettles RE, Gao M, Bifano M, et al. Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology. 2011;54:1956-1965.
    • (2011) Hepatology , vol.54 , pp. 1956-1965
    • Nettles, R.E.1    Gao, M.2    Bifano, M.3
  • 15
    • 84946512196 scopus 로고    scopus 로고
    • Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment
    • Garimella T, Wang R, Luo WL, et al. Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment. Antivir Ther. 2015;20:535-43.
    • (2015) Antivir Ther , vol.20 , pp. 535-543
    • Garimella, T.1    Wang, R.2    Luo, W.L.3
  • 16
    • 84906775992 scopus 로고    scopus 로고
    • The pharmacokinetics of daclatasvir and asunaprevir administered in combination in studies in healthy subjects and patients infected with hepatitis C virus
    • Eley T, Sevinsky H, Huang SP, et al. The pharmacokinetics of daclatasvir and asunaprevir administered in combination in studies in healthy subjects and patients infected with hepatitis C virus. Clin Drug Investig. 2014;34:661-671.
    • (2014) Clin Drug Investig , vol.34 , pp. 661-671
    • Eley, T.1    Sevinsky, H.2    Huang, S.P.3
  • 17
    • 84923841742 scopus 로고    scopus 로고
    • Ledipasvir-sofosbuvir: Interferon-/ribavirin-free regimen for chronic hepatitis C virus infection
    • Smith MA, Chan J, Mohammad RA. Ledipasvir-sofosbuvir: interferon-/ribavirin-free regimen for chronic hepatitis C virus infection. Ann Pharmacother. 2015;49:343-350.
    • (2015) Ann Pharmacother , vol.49 , pp. 343-350
    • Smith, M.A.1    Chan, J.2    Mohammad, R.A.3
  • 18
    • 84865285928 scopus 로고    scopus 로고
    • Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: A randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial
    • Pol S, Ghalib RH, Rustgi VK, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis. 2012;12:671-677.
    • (2012) Lancet Infect Dis , vol.12 , pp. 671-677
    • Pol, S.1    Ghalib, R.H.2    Rustgi, V.K.3
  • 19
    • 84932619401 scopus 로고    scopus 로고
    • Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: A randomised study
    • Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study. Gut. 2014;64:948-956.
    • (2014) Gut , vol.64 , pp. 948-956
    • Hezode, C.1    Hirschfield, G.M.2    Ghesquiere, W.3
  • 20
    • 84906350125 scopus 로고    scopus 로고
    • Daclatasvir combined with peginterferon alfa-2a and ribavirin in Japanese patients infected with hepatitis C genotype 1
    • Izumi N, Yokosuka O, Kawada N, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin in Japanese patients infected with hepatitis C genotype 1. Antivir Ther. 2014;19:501-510.
    • (2014) Antivir Ther , vol.19 , pp. 501-510
    • Izumi, N.1    Yokosuka, O.2    Kawada, N.3
  • 21
    • 84906344728 scopus 로고    scopus 로고
    • A randomized trial of daclatasvir with peginterferon alfa-2b and ribavirin for HCV genotype 1 infection
    • Suzuki F, Toyota J, Ikeda K, et al. A randomized trial of daclatasvir with peginterferon alfa-2b and ribavirin for HCV genotype 1 infection. Antivir Ther. 2014;19:491-499.
    • (2014) Antivir Ther , vol.19 , pp. 491-499
    • Suzuki, F.1    Toyota, J.2    Ikeda, K.3
  • 22
    • 84921415237 scopus 로고    scopus 로고
    • Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection
    • Dore GJ, Lawitz E, Hezode C, et al. Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection. Gastroenterology. 2015;148:355-366.e1.
    • (2015) Gastroenterology , vol.148
    • Dore, G.J.1    Lawitz, E.2    Hezode, C.3
  • 23
    • 84856159009 scopus 로고    scopus 로고
    • Preliminary study of two antiviral agents for hepatitis C genotype 1
    • Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216-224.
    • (2012) N Engl J Med , vol.366 , pp. 216-224
    • Lok, A.S.1    Gardiner, D.F.2    Lawitz, E.3
  • 24
    • 84894099866 scopus 로고    scopus 로고
    • Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders
    • Lok AS, Gardiner DF, Hezode C, et al. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatology. 2013;60:490-499.
    • (2013) J Hepatology , vol.60 , pp. 490-499
    • Lok, A.S.1    Gardiner, D.F.2    Hezode, C.3
  • 25
    • 84857395452 scopus 로고    scopus 로고
    • Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders
    • Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55:742-748.
    • (2012) Hepatology , vol.55 , pp. 742-748
    • Chayama, K.1    Takahashi, S.2    Toyota, J.3
  • 26
    • 84879693219 scopus 로고    scopus 로고
    • Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options
    • Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol. 2013;58:655-662.
    • (2013) J Hepatol , vol.58 , pp. 655-662
    • Suzuki, Y.1    Ikeda, K.2    Suzuki, F.3
  • 27
    • 84927786570 scopus 로고    scopus 로고
    • A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection
    • Hassanein T, Sims KD, Bennett M, et al. A randomized trial of daclatasvir in combination with asunaprevir and beclabuvir in patients with chronic hepatitis C virus genotype 4 infection. J Hepatol. 2015;62:1204-1206.
    • (2015) J Hepatol , vol.62 , pp. 1204-1206
    • Hassanein, T.1    Sims, K.D.2    Bennett, M.3
  • 28
    • 84892619580 scopus 로고    scopus 로고
    • Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection
    • Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-221.
    • (2014) N Engl J Med , vol.370 , pp. 211-221
    • Sulkowski, M.S.1    Gardiner, D.F.2    Rodriguez-Torres, M.3
  • 29
    • 84901595218 scopus 로고    scopus 로고
    • Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection
    • Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59:2083-2091.
    • (2014) Hepatology , vol.59 , pp. 2083-2091
    • Kumada, H.1    Suzuki, Y.2    Ikeda, K.3
  • 30
    • 84906814530 scopus 로고    scopus 로고
    • All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: A multinational, phase 3, multicohort study
    • Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet. 2014;384:1597-1605.
    • (2014) Lancet , vol.384 , pp. 1597-1605
    • Manns, M.1    Pol, S.2    Jacobson, I.M.3
  • 31
    • 84931576743 scopus 로고    scopus 로고
    • Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders
    • Jensen D, Sherman KE, Hezode C, et al. Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders. J Hepatol. 2015;63:30-37.
    • (2015) J Hepatol , vol.63 , pp. 30-37
    • Jensen, D.1    Sherman, K.E.2    Hezode, C.3
  • 32
    • 84925364974 scopus 로고    scopus 로고
    • All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase 3 study
    • Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase 3 study. Hepatology. 2015;61:1127-1135.
    • (2015) Hepatology , vol.61 , pp. 1127-1135
    • Nelson, D.R.1    Cooper, J.N.2    Lalezari, J.P.3
  • 33
    • 84939833091 scopus 로고    scopus 로고
    • Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1
    • Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373:714-725.
    • (2015) N Engl J Med , vol.373 , pp. 714-725
    • Wyles, D.L.1    Ruane, P.J.2    Sulkowski, M.S.3
  • 34
    • 84920941109 scopus 로고    scopus 로고
    • Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: Potent antiviral activity but no clinical benefit if treatment is given late
    • Pellicelli AM, Montalbano M, Lionetti R, et al. Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: potent antiviral activity but no clinical benefit if treatment is given late. Dig Liver Dis. 2014;46:923-927.
    • (2014) Dig Liver Dis , vol.46 , pp. 923-927
    • Pellicelli, A.M.1    Montalbano, M.2    Lionetti, R.3
  • 35
    • 84983160179 scopus 로고    scopus 로고
    • Safe and effective treatment with daclatasvir and asunaprevir in a liver transplant recipient with severe cholestatic hepatitis C
    • published online February 21
    • Ueda Y, Kaido T, Hatano E, Ohtsuru S, Uemoto S. Safe and effective treatment with daclatasvir and asunaprevir in a liver transplant recipient with severe cholestatic hepatitis C [published online February 21, 2015]. Hepatol Res. doi:10.1111/hepr.12509.
    • (2015) Hepatol Res
    • Ueda, Y.1    Kaido, T.2    Hatano, E.3    Ohtsuru, S.4    Uemoto, S.5
  • 36
    • 84924293707 scopus 로고    scopus 로고
    • Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate
    • Bifano M, Sevinsky H, Hwang C, et al. Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate. Antivir Ther. 2014;19:511-519.
    • (2014) Antivir Ther , vol.19 , pp. 511-519
    • Bifano, M.1    Sevinsky, H.2    Hwang, C.3
  • 37
    • 84925594123 scopus 로고    scopus 로고
    • Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/ naloxone
    • Garimella T, Wang R, Luo WL, et al. Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/ naloxone. J Int AIDS Soc. 2014;17(4, suppl 3):19628.
    • (2014) J Int AIDS Soc , vol.17 , Issue.4 , pp. 19628
    • Garimella, T.1    Wang, R.2    Luo, W.L.3
  • 38
    • 84891829801 scopus 로고    scopus 로고
    • Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: Ritonavir-boosted atazanavir, efavirenz and tenofovir
    • Bifano M, Hwang C, Oosterhuis B, et al. Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir. Antivir Ther. 2013;18:931-940.
    • (2013) Antivir Ther , vol.18 , pp. 931-940
    • Bifano, M.1    Hwang, C.2    Oosterhuis, B.3
  • 40
    • 84936847226 scopus 로고    scopus 로고
    • The effect of coadministration of the proton-pump inhibitor omeprazole on the pharmacokinetics of daclatasvir in healthy subjects
    • Bifano M, Connolly S, Hwang C, Sevinsky H, Bertz R. The effect of coadministration of the proton-pump inhibitor omeprazole on the pharmacokinetics of daclatasvir in healthy subjects. J Hepatol. 2013;58:S229-S407.
    • (2013) J Hepatol , vol.58 , pp. S229-S407
    • Bifano, M.1    Connolly, S.2    Hwang, C.3    Sevinsky, H.4    Bertz, R.5
  • 41
    • 84921433851 scopus 로고    scopus 로고
    • Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1
    • Kosaka K, Imamura M, Hayes CN, et al. Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1. J Viral Hepat. 2015;22:156-163.
    • (2015) J Viral Hepat , vol.22 , pp. 156-163
    • Kosaka, K.1    Imamura, M.2    Hayes, C.N.3
  • 42
    • 84906087908 scopus 로고    scopus 로고
    • Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: Implications for cross-genotype activity
    • Wang C, Jia L, O’Boyle DR II, et al. Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity. Antimicrob Agents Chemother. 2014;58:5155-5163.
    • (2014) Antimicrob Agents Chemother , vol.58 , pp. 5155-5163
    • Wang, C.1    Jia, L.2    O’Boyle, D.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.