메뉴 건너뛰기




Volumn 12, Issue 2, 2009, Pages 152-159

Efficacy and safety of dutasteride, tamsulosin and their combination in a subpopulation of the CombAT study: 2-year results in Asian men with moderate-to-severe BPH

Author keywords

[No Author keywords available]

Indexed keywords

DUTASTERIDE; TAMSULOSIN;

EID: 67349091472     PISSN: 13657852     EISSN: 14765608     Source Type: Journal    
DOI: 10.1038/pcan.2008.49     Document Type: Article
Times cited : (18)

References (48)
  • 1
    • 67349156553 scopus 로고    scopus 로고
    • National Kidney and Urologic Diseases Information Clearing House NKUDIC, Benign prostatic hyperplasia, Cited 10 January 2008, Available from
    • National Kidney and Urologic Diseases Information Clearing House (NKUDIC). Prostate enlargement: Benign prostatic hyperplasia. [Cited 10 January 2008]; Available from: http://kidney.niddk.nih.gov/kudiseases/ pubs/prostateenlargement/.
    • Prostate enlargement
  • 2
    • 34447129021 scopus 로고    scopus 로고
    • Nocturia, nocturia indices and variables from frequency-volume charts are significantly different in Asian and Caucasian men with lower urinary tract symptoms: A prospective comparison study
    • Mariappan P, Turner KJ, Sothilingam S, Rajan P, Sundram M, Stewart LH. Nocturia, nocturia indices and variables from frequency-volume charts are significantly different in Asian and Caucasian men with lower urinary tract symptoms: A prospective comparison study. BJU Int 2007; 100: 332-336.
    • (2007) BJU Int , vol.100 , pp. 332-336
    • Mariappan, P.1    Turner, K.J.2    Sothilingam, S.3    Rajan, P.4    Sundram, M.5    Stewart, L.H.6
  • 3
    • 8044231306 scopus 로고    scopus 로고
    • Epidemiologic survey of lower urinary tract symptoms in Asia and Australia using the international prostate symptom score
    • Homma Y, Kawabe K, Tsukamoto T, Yamanaka H, Okada K, Okajima E et al Epidemiologic survey of lower urinary tract symptoms in Asia and Australia using the international prostate symptom score. Int J Urol 1997; 4: 40-46.
    • (1997) Int J Urol , vol.4 , pp. 40-46
    • Homma, Y.1    Kawabe, K.2    Tsukamoto, T.3    Yamanaka, H.4    Okada, K.5    Okajima, E.6
  • 5
    • 0042145992 scopus 로고    scopus 로고
    • Etiology, pathophysiology, epidemiology and natural history of BPH
    • Walsh P ed, WB Saunders: Philadelphia
    • Roehrborn C, McConnell JD. Etiology, pathophysiology, epidemiology and natural history of BPH. In: Walsh P (ed). Campbell's Urology. WB Saunders: Philadelphia, 2002, pp 1297-1336.
    • (2002) Campbell's Urology , pp. 1297-1336
    • Roehrborn, C.1    McConnell, J.D.2
  • 6
    • 0028949115 scopus 로고
    • Serum prostate-specific antigen in a community-based population of healthy Japanese men: Lower values than for similarly aged white men
    • Oesterling JE, Kumamoto Y, Tsukamoto T, Girman CJ, Guess HA, Masumori N et al. Serum prostate-specific antigen in a community-based population of healthy Japanese men: Lower values than for similarly aged white men. Br J Urol 1995; 75: 347-353.
    • (1995) Br J Urol , vol.75 , pp. 347-353
    • Oesterling, J.E.1    Kumamoto, Y.2    Tsukamoto, T.3    Girman, C.J.4    Guess, H.A.5    Masumori, N.6
  • 7
    • 0033664072 scopus 로고    scopus 로고
    • Ethnic differences in the age-related distribution of serum prostatespecific antigen values: A study in a healthy Korean male population
    • Lee SE, Kwak C, Park MS, Lee CH, Kang W, Oh SJ. Ethnic differences in the age-related distribution of serum prostatespecific antigen values: A study in a healthy Korean male population. Urology 2000; 56: 1007-1010.
    • (2000) Urology , vol.56 , pp. 1007-1010
    • Lee, S.E.1    Kwak, C.2    Park, M.S.3    Lee, C.H.4    Kang, W.5    Oh, S.J.6
  • 8
    • 0029998790 scopus 로고    scopus 로고
    • Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: Results of community based studies in 2 countries
    • Masumori N, Tsukamoto T, Kumamoto Y, Miyake H, Rhodes T, Girman CJ et al. Japanese men have smaller prostate volumes but comparable urinary flow rates relative to American men: Results of community based studies in 2 countries. J Urol 1996; 155: 1324-1327.
    • (1996) J Urol , vol.155 , pp. 1324-1327
    • Masumori, N.1    Tsukamoto, T.2    Kumamoto, Y.3    Miyake, H.4    Rhodes, T.5    Girman, C.J.6
  • 10
    • 1542784494 scopus 로고    scopus 로고
    • Agespecific reference ranges for serum prostate-specific antigen in Chinese men
    • Wang MZ, Gao ZW, He DL, Chen XF, He H,Wang WS et al. Agespecific reference ranges for serum prostate-specific antigen in Chinese men. Zhonghua Yi Xue Za Zhi 2003; 83: 1665-1667.
    • (2003) Zhonghua Yi Xue Za Zhi , vol.83 , pp. 1665-1667
    • Wang, M.Z.1    Gao, Z.W.2    He, D.L.3    Chen, X.F.4    He, H.5    Wang, W.S.6
  • 11
  • 13
    • 2442545242 scopus 로고    scopus 로고
    • Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor
    • Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab 2004; 89: 2179-2184.
    • (2004) J Clin Endocrinol Metab , vol.89 , pp. 2179-2184
    • Clark, R.V.1    Hermann, D.J.2    Cunningham, G.R.3    Wilson, T.H.4    Morrill, B.B.5    Hobbs, S.6
  • 15
    • 1642266520 scopus 로고    scopus 로고
    • 5-Alpha reductase inhibition provides superior benefits to alpha blockade by preventing AUR and BPH-related surgery
    • discussion 626-627
    • Boyle P, Roehrborn C, Harkaway R, Logie J, de la Rosette J, Emberton M. 5-Alpha reductase inhibition provides superior benefits to alpha blockade by preventing AUR and BPH-related surgery. Eur Urol 2004; 45: 620-626; [discussion 626-627].
    • (2004) Eur Urol , vol.45 , pp. 620-626
    • Boyle, P.1    Roehrborn, C.2    Harkaway, R.3    Logie, J.4    de la Rosette, J.5    Emberton, M.6
  • 16
    • 0141572168 scopus 로고    scopus 로고
    • Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride
    • Barkin J, Guimaraes M, Jacobi G, Pushkar D, Taylor S, van Vierssen Trip OB. Alpha-blocker therapy can be withdrawn in the majority of men following initial combination therapy with the dual 5alpha-reductase inhibitor dutasteride. Eur Urol 2003; 44: 461-466.
    • (2003) Eur Urol , vol.44 , pp. 461-466
    • Barkin, J.1    Guimaraes, M.2    Jacobi, G.3    Pushkar, D.4    Taylor, S.5    van Vierssen Trip, O.B.6
  • 17
    • 1642383576 scopus 로고    scopus 로고
    • Optimising the medical management of benign prostatic hyperplasia
    • Marberger M, Harkaway R, de la Rosette J. Optimising the medical management of benign prostatic hyperplasia. Eur Urol 2004; 45 411-419.
    • (2004) Eur Urol , vol.45 , pp. 411-419
    • Marberger, M.1    Harkaway, R.2    de la Rosette, J.3
  • 18
    • 4544285381 scopus 로고    scopus 로고
    • Dihydrotestosterone and the prostate: The scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia
    • Andriole G, Bruchovsky N, Chung LW, Matsumoto AM, Rittmaster R, Roehrborn C et al. Dihydrotestosterone and the prostate: The scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol 2004; 172: 1399-1403.
    • (2004) J Urol , vol.172 , pp. 1399-1403
    • Andriole, G.1    Bruchovsky, N.2    Chung, L.W.3    Matsumoto, A.M.4    Rittmaster, R.5    Roehrborn, C.6
  • 19
    • 0037377691 scopus 로고    scopus 로고
    • The role of dihydrotestosterone in benign prostatic hyperplasia
    • Carson III C, Rittmaster R. The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 2003; 61: 2-7.
    • (2003) Urology , vol.61 , pp. 2-7
    • Carson III, C.1    Rittmaster, R.2
  • 20
    • 33746580539 scopus 로고    scopus 로고
    • Dutasteride improves objective and subjective disease measures in men with benign prostatic hyperplasia and modest or severe prostate enlargement
    • discussion 1050
    • Gittelman M, Ramsdell J, Young J, McNicholas T. Dutasteride improves objective and subjective disease measures in men with benign prostatic hyperplasia and modest or severe prostate enlargement. J Urol 2006; 176: 1045-1050; [discussion 1050].
    • (2006) J Urol , vol.176 , pp. 1045-1050
    • Gittelman, M.1    Ramsdell, J.2    Young, J.3    McNicholas, T.4
  • 21
    • 34547395306 scopus 로고    scopus 로고
    • Combination medical therapy for lower urinary tract symptoms and benign prostatic hyperplasia
    • Roehrborn CG. Combination medical therapy for lower urinary tract symptoms and benign prostatic hyperplasia. Rev Urol 2005; 7 (Suppl 8): S43-S51.
    • (2005) Rev Urol , vol.7 , Issue.SUPPL. 8
    • Roehrborn, C.G.1
  • 22
    • 0036754256 scopus 로고    scopus 로고
    • Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia
    • Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60: 434-441.
    • (2002) Urology , vol.60 , pp. 434-441
    • Roehrborn, C.G.1    Boyle, P.2    Nickel, J.C.3    Hoefner, K.4    Andriole, G.5
  • 23
    • 0347882750 scopus 로고    scopus 로고
    • Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia
    • McConnell JD, Roehrborn CG, Bautista OM, Andriole Jr GL, Dixon CM, Kusek JW, et al., Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: 2387-2398.
    • (2003) N Engl J Med , vol.349 , pp. 2387-2398
    • McConnell, J.D.1    Roehrborn, C.G.2    Bautista, O.M.3    Andriole Jr, G.L.4    Dixon, C.M.5    Kusek, J.W.6
  • 24
    • 38849201263 scopus 로고    scopus 로고
    • CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study
    • Roehrborn CG, Siami P, Barkin J, Damiaão R, Major-Walker K, Morrill B, et al., CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol 2007; 179: 616-621.
    • (2007) J Urol , vol.179 , pp. 616-621
    • Roehrborn, C.G.1    Siami, P.2    Barkin, J.3    Damiaão, R.4    Major-Walker, K.5    Morrill, B.6
  • 25
    • 34848860581 scopus 로고    scopus 로고
    • CombAT study group. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: The CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design
    • Siami P, Roehrborn CG, Barkin J, Damiao R, Wyczolkowski M, Duggan A, et al., CombAT study group. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: The CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials 2007; 28: 770-779.
    • (2007) Contemp Clin Trials , vol.28 , pp. 770-779
    • Siami, P.1    Roehrborn, C.G.2    Barkin, J.3    Damiao, R.4    Wyczolkowski, M.5    Duggan, A.6
  • 27
    • 0032101597 scopus 로고    scopus 로고
    • Long-term evaluation of tamsulosin in benign prostatic hyperplasia: Placebo-controlled, double-blind extension of phase III trial. Tamsulosin Investigator Group
    • Lepor H. Long-term evaluation of tamsulosin in benign prostatic hyperplasia: Placebo-controlled, double-blind extension of phase III trial. Tamsulosin Investigator Group. Urology 1998; 51: 901-906.
    • (1998) Urology , vol.51 , pp. 901-906
    • Lepor, H.1
  • 28
    • 0032100513 scopus 로고    scopus 로고
    • Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group
    • Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology 1998; 51: 892-900.
    • (1998) Urology , vol.51 , pp. 892-900
    • Lepor, H.1
  • 29
    • 0035123154 scopus 로고    scopus 로고
    • Long-term, open-label, phase III multicenter study of tamsulosin in benign prostatic hyperplasia
    • Narayan P, Lepor H. Long-term, open-label, phase III multicenter study of tamsulosin in benign prostatic hyperplasia. Urology 2001; 57 466-470.
    • (2001) Urology , vol.57 , pp. 466-470
    • Narayan, P.1    Lepor, H.2
  • 30
    • 16244389702 scopus 로고    scopus 로고
    • Doxazosin for benign prostatic hyperplasia: An open-label, baseline-controlled study in Korean general practice
    • Chung BH, Hong SJ, Lee MS. Doxazosin for benign prostatic hyperplasia: an open-label, baseline-controlled study in Korean general practice. Int J Urol 2005; 12: 159-165.
    • (2005) Int J Urol , vol.12 , pp. 159-165
    • Chung, B.H.1    Hong, S.J.2    Lee, M.S.3
  • 31
  • 32
    • 0036868264 scopus 로고    scopus 로고
    • Comparison of tamsulosin and finasteride for lower urinary tract symptoms associated with benign prostatic hyperplasia in Korean patients
    • Lee E. Comparison of tamsulosin and finasteride for lower urinary tract symptoms associated with benign prostatic hyperplasia in Korean patients. J Int Med Res 2002; 30: 584-590.
    • (2002) J Int Med Res , vol.30 , pp. 584-590
    • Lee, E.1
  • 33
    • 0346732072 scopus 로고    scopus 로고
    • Efficacy of low-dose tamsulosin in chinese patients with symptomatic benign prostatic hyperplasia
    • Li NC, Chen S, Yang XH, Du LD, Wang JY, Na YQ. Efficacy of low-dose tamsulosin in chinese patients with symptomatic benign prostatic hyperplasia. Clin Drug Investig 2003; 23: 781-787.
    • (2003) Clin Drug Investig , vol.23 , pp. 781-787
    • Li, N.C.1    Chen, S.2    Yang, X.H.3    Du, L.D.4    Wang, J.Y.5    Na, Y.Q.6
  • 34
    • 1042267993 scopus 로고    scopus 로고
    • Efficacy of low-dose tamsulosin on lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A nonblind multicentre korean study
    • Park CH, Chang HS, Oh BR, Kim HJ, Sul CK, Chung SK et al. Efficacy of low-dose tamsulosin on lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A nonblind multicentre korean study. Clin Drug Investig 2004; 24: 41-47.
    • (2004) Clin Drug Investig , vol.24 , pp. 41-47
    • Park, C.H.1    Chang, H.S.2    Oh, B.R.3    Kim, H.J.4    Sul, C.K.5    Chung, S.K.6
  • 35
    • 33748772231 scopus 로고    scopus 로고
    • Clinical impact of tamsulosin on generic and symptom-specific quality of life for benign prostatic hyperplasia patients: Using international prostate symptom score and Rand Medical Outcomes Study 36-item Health Survey
    • Suzuki H, Yano M, Awa Y, Nakatsu H, Egoshi K, Mikami K et al. Clinical impact of tamsulosin on generic and symptom-specific quality of life for benign prostatic hyperplasia patients: Using international prostate symptom score and Rand Medical Outcomes Study 36-item Health Survey. Int J Urol 2006; 13: 1202-1206.
    • (2006) Int J Urol , vol.13 , pp. 1202-1206
    • Suzuki, H.1    Yano, M.2    Awa, Y.3    Nakatsu, H.4    Egoshi, K.5    Mikami, K.6
  • 36
    • 0029834709 scopus 로고    scopus 로고
    • Treating benign prostatic hyperplasia with finasteride in Chinese men: One-year experience
    • Chueh SC, Yu HJ, Chiu TY, Huang CY, Lai MK. Treating benign prostatic hyperplasia with finasteride in Chinese men: One-year experience. J Formos Med Assoc 1996; 95: 650-652.
    • (1996) J Formos Med Assoc , vol.95 , pp. 650-652
    • Chueh, S.C.1    Yu, H.J.2    Chiu, T.Y.3    Huang, C.Y.4    Lai, M.K.5
  • 37
    • 0034184338 scopus 로고    scopus 로고
    • A higher PSA-density cutoff level in patients with intermediate PSA values for the early detection of prostate cancer
    • Mochtar CA, Rahardjo D, Umbas R. A higher PSA-density cutoff level in patients with intermediate PSA values for the early detection of prostate cancer. Gan To Kagaku Ryoho 2000; 27 (Suppl 2): 514-522.
    • (2000) Gan To Kagaku Ryoho , vol.27 , Issue.SUPPL. 2 , pp. 514-522
    • Mochtar, C.A.1    Rahardjo, D.2    Umbas, R.3
  • 38
    • 12544252480 scopus 로고    scopus 로고
    • Relationship between prostate specific antigen and indexes of prostate volume in Japanese men
    • Gupta A, Aragaki C, Gotoh M, Masumori N, Ohshima S, Tsukamoto T et al Relationship between prostate specific antigen and indexes of prostate volume in Japanese men. J Urol 2005; 173: 503-506.
    • (2005) J Urol , vol.173 , pp. 503-506
    • Gupta, A.1    Aragaki, C.2    Gotoh, M.3    Masumori, N.4    Ohshima, S.5    Tsukamoto, T.6
  • 39
    • 33744831972 scopus 로고    scopus 로고
    • Correlation between serum prostate specific antigen and prostate volume in Taiwanese men with biopsy proven benign prostatic hyperplasia
    • Chang YL, Lin AT, Chen KK, Chang YH, Wu HH, Kuo JY et al. Correlation between serum prostate specific antigen and prostate volume in Taiwanese men with biopsy proven benign prostatic hyperplasia. J Urol 2006; 176: 196-199.
    • (2006) J Urol , vol.176 , pp. 196-199
    • Chang, Y.L.1    Lin, A.T.2    Chen, K.K.3    Chang, Y.H.4    Wu, H.H.5    Kuo, J.Y.6
  • 40
    • 0032588595 scopus 로고    scopus 로고
    • Iehle C, Radvanyi F, Gil Diez de Medina S, Ouafik LH, Gérard H, Chopin D et al. Differences in steroid 5alpha-reductase isoenzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol 1999; 68: 189-195.
    • Iehle C, Radvanyi F, Gil Diez de Medina S, Ouafik LH, Gérard H, Chopin D et al. Differences in steroid 5alpha-reductase isoenzymes expression between normal and pathological human prostate tissue. J Steroid Biochem Mol Biol 1999; 68: 189-195.
  • 41
    • 0030249241 scopus 로고    scopus 로고
    • Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: Meta-analysis of randomized clinical trials
    • Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48 398-405.
    • (1996) Urology , vol.48 , pp. 398-405
    • Boyle, P.1    Gould, A.L.2    Roehrborn, C.G.3
  • 43
    • 0018150495 scopus 로고
    • Origin and evolution of benign prostatic enlargement
    • McNeal JE. Origin and evolution of benign prostatic enlargement. Invest Urol 1978; 15: 340-345.
    • (1978) Invest Urol , vol.15 , pp. 340-345
    • McNeal, J.E.1
  • 44
    • 0035205361 scopus 로고    scopus 로고
    • Racial differences in cellular composition of benign prostatic hyperplasia
    • Aoki Y, Arai Y, Maeda H, Okubo K, Shinohara K. Racial differences in cellular composition of benign prostatic hyperplasia. Prostate 2001; 49: 243-250.
    • (2001) Prostate , vol.49 , pp. 243-250
    • Aoki, Y.1    Arai, Y.2    Maeda, H.3    Okubo, K.4    Shinohara, K.5
  • 45
    • 0032836503 scopus 로고    scopus 로고
    • The relative amount of epithelium, muscle, connective tissue and lumen in prostatic hyperplasia as a function of the mass of tissue resected
    • Schuster GA, Schuster TG. The relative amount of epithelium, muscle, connective tissue and lumen in prostatic hyperplasia as a function of the mass of tissue resected. J Urol 1999; 161: 1168-1173.
    • (1999) J Urol , vol.161 , pp. 1168-1173
    • Schuster, G.A.1    Schuster, T.G.2
  • 46
    • 0033252881 scopus 로고    scopus 로고
    • Racial differences in the androgen/androgen receptor pathway in prostate cancer
    • Pettaway CA. Racial differences in the androgen/androgen receptor pathway in prostate cancer. J Natl Med Assoc 1999; 91: 653-660.
    • (1999) J Natl Med Assoc , vol.91 , pp. 653-660
    • Pettaway, C.A.1
  • 47
    • 18744393366 scopus 로고    scopus 로고
    • Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4
    • Zeigler-Johnson CM, Walker AH, Mancke B, Spangler E, Jalloh M, McBride S et al. Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4. Hum Hered 2002; 54 13-21.
    • (2002) Hum Hered , vol.54 , pp. 13-21
    • Zeigler-Johnson, C.M.1    Walker, A.H.2    Mancke, B.3    Spangler, E.4    Jalloh, M.5    McBride, S.6
  • 48
    • 33644890470 scopus 로고    scopus 로고
    • Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: A multicentre study
    • Chung BH, Hong SJ, Cho JS, Seong DH. Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: A multicentre study. BJU Int 2006; 97 742-746
    • (2006) BJU Int , vol.97 , pp. 742-746
    • Chung, B.H.1    Hong, S.J.2    Cho, J.S.3    Seong, D.H.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.