메뉴 건너뛰기




Volumn 30, Issue 3, 2008, Pages 482-498

The effects of amlodipine and enalapril on renal function in adults with hypertension and nondiabetic nephropathies: A 3-year, randomized, multicenter, double-blind, placebo-controlled study

Author keywords

angiotensin converting enzyme inhibitors; calcium channel blockers; chronic renal failure; diuretics; glomerular filtration rate; proteinuria; randomized placebo controlled trial

Indexed keywords

ALPHA ADRENERGIC RECEPTOR BLOCKING AGENT; AMLODIPINE; ANGIOTENSIN RECEPTOR ANTAGONIST; ATENOLOL; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CALCIUM CHANNEL BLOCKING AGENT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; DOXAZOSIN; EDETATE CHROMIUM CR 51; ENALAPRIL; FUROSEMIDE; METHYLDOPA; PLACEBO; PRAZOSIN; RILMENIDINE; TORASEMIDE; VASODILATOR AGENT;

EID: 41649101421     PISSN: 01492918     EISSN: 1879114X     Source Type: Journal    
DOI: 10.1016/j.clinthera.2008.03.006     Document Type: Article
Times cited : (33)

References (43)
  • 1
    • 0035912555 scopus 로고    scopus 로고
    • Progression, remission, regression of chronic renal diseases
    • Ruggenenti P., Schieppati A., and Remuzzi G. Progression, remission, regression of chronic renal diseases. Lancet 357 (2001) 1601-1608
    • (2001) Lancet , vol.357 , pp. 1601-1608
    • Ruggenenti, P.1    Schieppati, A.2    Remuzzi, G.3
  • 2
    • 0141789624 scopus 로고    scopus 로고
    • Progression of chronic kidney disease: The role of blood pressure control, proteinuria, and angiotensinconverting enzyme inhibition: A patient-level metaanalysis
    • for the AIPRD Study Group
    • Jafar T., Stark P., Schmid C., et al., for the AIPRD Study Group. Progression of chronic kidney disease: The role of blood pressure control, proteinuria, and angiotensinconverting enzyme inhibition: A patient-level metaanalysis. Ann Intern Med 139 (2003) 244-252
    • (2003) Ann Intern Med , vol.139 , pp. 244-252
    • Jafar, T.1    Stark, P.2    Schmid, C.3
  • 3
    • 28844504752 scopus 로고    scopus 로고
    • Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: Systematic review and meta-analysis
    • Casas J., Chua W., Loukogeorgakis S., et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: Systematic review and meta-analysis. Lancet 366 (2005) 2026-2033
    • (2005) Lancet , vol.366 , pp. 2026-2033
    • Casas, J.1    Chua, W.2    Loukogeorgakis, S.3
  • 4
    • 33748316445 scopus 로고    scopus 로고
    • The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease
    • Remuzzi G., Perico N., Macia M., and Ruggenenti P. The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl 99 (2005) S57-S65
    • (2005) Kidney Int Suppl , vol.99
    • Remuzzi, G.1    Perico, N.2    Macia, M.3    Ruggenenti, P.4
  • 5
    • 33847023386 scopus 로고    scopus 로고
    • Ca2+ channel subtypes and pharmacology in the kidney
    • Hayashi K., Wakino S., Sugano N., et al. Ca2+ channel subtypes and pharmacology in the kidney. Circ Res 100 (2007) 342-353
    • (2007) Circ Res , vol.100 , pp. 342-353
    • Hayashi, K.1    Wakino, S.2    Sugano, N.3
  • 7
    • 0027517659 scopus 로고
    • The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy
    • for the Collaborative Study Group. [published correction appears in N Engl J Med 1993;330:152]
    • Lewis E., Hunsicker L., Bain R., Rohde R., and for the Collaborative Study Group. The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy. [published correction appears in N Engl J Med 1993;330:152]. N Engl J Med 329 (1993) 1456-1462
    • (1993) N Engl J Med , vol.329 , pp. 1456-1462
    • Lewis, E.1    Hunsicker, L.2    Bain, R.3    Rohde, R.4
  • 8
    • 15844368318 scopus 로고    scopus 로고
    • Effect of the angiotensin-convertingenzyme inhibitor benazepril on the progression of chronic renal insufficiency
    • for the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group
    • Maschio G., Alberti D., Janin G., et al., for the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Effect of the angiotensin-convertingenzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334 (1996) 939-945
    • (1996) N Engl J Med , vol.334 , pp. 939-945
    • Maschio, G.1    Alberti, D.2    Janin, G.3
  • 9
    • 0030604561 scopus 로고    scopus 로고
    • Randomised placebocontrolled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy
    • The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia)
    • The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebocontrolled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349 (1997) 1857-1863
    • (1997) Lancet , vol.349 , pp. 1857-1863
  • 10
    • 0033620788 scopus 로고    scopus 로고
    • Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria
    • Ruggenenti P., Perna A., Gherardi G., et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 354 (1999) 359-364
    • (1999) Lancet , vol.354 , pp. 359-364
    • Ruggenenti, P.1    Perna, A.2    Gherardi, G.3
  • 11
    • 0035922444 scopus 로고    scopus 로고
    • The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes
    • for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group
    • Parving H., Lehnert H., Bröchner-Mortensen J., et al., for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345 (2001) 870-878
    • (2001) N Engl J Med , vol.345 , pp. 870-878
    • Parving, H.1    Lehnert, H.2    Bröchner-Mortensen, J.3
  • 12
    • 0035922441 scopus 로고    scopus 로고
    • Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy
    • for the RENAAL Study Investigators
    • Brenner B., Cooper M., de Zeeuw D., et al., for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345 (2001) 861-869
    • (2001) N Engl J Med , vol.345 , pp. 861-869
    • Brenner, B.1    Cooper, M.2    de Zeeuw, D.3
  • 13
    • 0035922447 scopus 로고    scopus 로고
    • Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes
    • for the Collaborative Study Group
    • Lewis E., Hunsicker L., Clarke W., et al., for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345 (2001) 851-860
    • (2001) N Engl J Med , vol.345 , pp. 851-860
    • Lewis, E.1    Hunsicker, L.2    Clarke, W.3
  • 14
    • 30444452987 scopus 로고    scopus 로고
    • Efficacy and safety of benazepril for advanced chronic renal insufficiency
    • Hou F., Zhang X., Zhang G., et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 354 (2006) 131-140
    • (2006) N Engl J Med , vol.354 , pp. 131-140
    • Hou, F.1    Zhang, X.2    Zhang, G.3
  • 15
    • 0026649651 scopus 로고
    • Long-term comparison between captopril and nifedipine in the progression of renal insufficiency
    • Zucchelli P., Zuccalà A., Borghi M., et al. Long-term comparison between captopril and nifedipine in the progression of renal insufficiency. Kidney Int 42 (1992) 452-458
    • (1992) Kidney Int , vol.42 , pp. 452-458
    • Zucchelli, P.1    Zuccalà, A.2    Borghi, M.3
  • 16
    • 0034805993 scopus 로고    scopus 로고
    • A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease
    • for the Investigators of the ESPIRAL Study (Efecto del tratamiento antihipertensivo Sobre la Progresión de la Insuficiencia RenAL en pacientes no diabéticos)
    • Marin R., Ruilope L., Aljama P., et al., for the Investigators of the ESPIRAL Study (Efecto del tratamiento antihipertensivo Sobre la Progresión de la Insuficiencia RenAL en pacientes no diabéticos). A random comparison of fosinopril and nifedipine GITS in patients with primary renal disease. J Hypertens 19 (2001) 1871-1876
    • (2001) J Hypertens , vol.19 , pp. 1871-1876
    • Marin, R.1    Ruilope, L.2    Aljama, P.3
  • 17
    • 0035164669 scopus 로고    scopus 로고
    • The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: The Nephros Study
    • Herlitz H., Harris K., Risler T., et al. The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: The Nephros Study. Nephrol Dial Transplant 16 (2001) 2158-2165
    • (2001) Nephrol Dial Transplant , vol.16 , pp. 2158-2165
    • Herlitz, H.1    Harris, K.2    Risler, T.3
  • 18
    • 0035816018 scopus 로고    scopus 로고
    • Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial
    • for the African American Study of Kidney Disease and Hypertension (AASK) Study Group
    • Agodoa L., Appel L., Bakris G., et al., for the African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. JAMA 285 (2001) 2719-2728
    • (2001) JAMA , vol.285 , pp. 2719-2728
    • Agodoa, L.1    Appel, L.2    Bakris, G.3
  • 19
    • 0037145856 scopus 로고    scopus 로고
    • Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial
    • for the African American Study of Kidney Disease and Hypertension Study Group. [published correction appears in JAMA 2006;295:2726]
    • Wright Jr. J., Bakris G., Greene T., et al., for the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. [published correction appears in JAMA 2006;295:2726]. JAMA 288 (2002) 2421-2431
    • (2002) JAMA , vol.288 , pp. 2421-2431
    • Wright Jr., J.1    Bakris, G.2    Greene, T.3
  • 20
    • 0344373794 scopus 로고    scopus 로고
    • Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
    • ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. [published corrections appear in JAMA 2003;289:178 and JAMA. 2004;291:2196]
    • ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). [published corrections appear in JAMA 2003;289:178 and JAMA. 2004;291:2196]. JAMA 288 (2002) 2981-2997
    • (2002) JAMA , vol.288 , pp. 2981-2997
  • 21
    • 20244371503 scopus 로고    scopus 로고
    • Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: A report from the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
    • Rahman M., Pressel S., Davis B., et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: A report from the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 165 (2005) 936-946
    • (2005) Arch Intern Med , vol.165 , pp. 936-946
    • Rahman, M.1    Pressel, S.2    Davis, B.3
  • 22
    • 0030713021 scopus 로고    scopus 로고
    • The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
    • [published correction appears in Arch Intern Med. 1998; 158:573]
    • The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. [published correction appears in Arch Intern Med. 1998; 158:573]. Arch Intern Med 157 (1997) 2413-2446
    • (1997) Arch Intern Med , vol.157 , pp. 2413-2446
  • 25
    • 20544471164 scopus 로고    scopus 로고
    • Diuretic and enhanced sodium restriction results in improved anti-proteinuric response to RAS blocking agents
    • Esnault V., Ekhlas A., Delcroix C., et al. Diuretic and enhanced sodium restriction results in improved anti-proteinuric response to RAS blocking agents. J Am Soc Nephrol 16 (2005) 474-481
    • (2005) J Am Soc Nephrol , vol.16 , pp. 474-481
    • Esnault, V.1    Ekhlas, A.2    Delcroix, C.3
  • 26
    • 0344468054 scopus 로고    scopus 로고
    • Angiotensin-convertingenzyme inhibitors and diuretics for hypertension
    • Esnault V. Angiotensin-convertingenzyme inhibitors and diuretics for hypertension. N Engl J Med 349 (2003) 90-93
    • (2003) N Engl J Med , vol.349 , pp. 90-93
    • Esnault, V.1
  • 27
    • 0038188560 scopus 로고    scopus 로고
    • Retarding progression of chronic renal disease: The neglected issue of residual proteinuria
    • for the GISEN Group Investigators
    • Ruggenenti P., Perna A., Remuzzi G., and for the GISEN Group Investigators. Retarding progression of chronic renal disease: The neglected issue of residual proteinuria. Kidney Int 63 (2003) 2254-2261
    • (2003) Kidney Int , vol.63 , pp. 2254-2261
    • Ruggenenti, P.1    Perna, A.2    Remuzzi, G.3
  • 28
    • 0035902622 scopus 로고    scopus 로고
    • Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data
    • [published correction appears in Ann Intern Med. 2002;137:299]
    • Jafar T., Schmid C., Landa M., et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. [published correction appears in Ann Intern Med. 2002;137:299]. Ann Intern Med 135 (2001) 73-87
    • (2001) Ann Intern Med , vol.135 , pp. 73-87
    • Jafar, T.1    Schmid, C.2    Landa, M.3
  • 29
    • 0037143580 scopus 로고    scopus 로고
    • Effect of angiotensin-converting enzyme inhibitors on progression of nondiabetic renal disease
    • Jafar T., Schmid C., and Levey A. Effect of angiotensin-converting enzyme inhibitors on progression of nondiabetic renal disease. Ann Intern Med 137 (2002) 298-299
    • (2002) Ann Intern Med , vol.137 , pp. 298-299
    • Jafar, T.1    Schmid, C.2    Levey, A.3
  • 30
    • 0031748479 scopus 로고    scopus 로고
    • The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide
    • Buter H., Hemmelder M., Navis G., et al. The blunting of the antiproteinuric efficacy of ACE inhibition by high sodium intake can be restored by hydrochlorothiazide. Nephrol Dial Transplant 13 (1998) 1682-1685
    • (1998) Nephrol Dial Transplant , vol.13 , pp. 1682-1685
    • Buter, H.1    Hemmelder, M.2    Navis, G.3
  • 31
    • 0037527647 scopus 로고    scopus 로고
    • 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension
    • European Society of Hypertension-European Society of Cardiology Guidelines Committee. [published corrections appear in J Hypertens 2003;21:2203-2204 and J Hypertens. 2004;22:435]
    • European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. [published corrections appear in J Hypertens 2003;21:2203-2204 and J Hypertens. 2004;22:435]. J Hypertens 21 (2003) 1011-1053
    • (2003) J Hypertens , vol.21 , pp. 1011-1053
  • 32
    • 0034115706 scopus 로고    scopus 로고
    • Renoprotective properties of angiotensin-converting enzyme inhibitors: Proofs and limits?
    • Esnault V. Renoprotective properties of angiotensin-converting enzyme inhibitors: Proofs and limits?. Nephron 85 (2000) 183-184
    • (2000) Nephron , vol.85 , pp. 183-184
    • Esnault, V.1
  • 33
    • 0024588103 scopus 로고
    • Renal vascular effects of antihypertensive therapy in uninephrectomized SHR
    • Dworkin L., Grosser M., Feiner H., et al. Renal vascular effects of antihypertensive therapy in uninephrectomized SHR. Kidney Int 35 (1989) 790-798
    • (1989) Kidney Int , vol.35 , pp. 790-798
    • Dworkin, L.1    Grosser, M.2    Feiner, H.3
  • 34
    • 0030448983 scopus 로고    scopus 로고
    • Antihypertensive drug treatment in chronic renal allograft rejection in the rat. Effect on structure and function
    • Benediktsson H., Chea R., Davidoff A., and Paul L. Antihypertensive drug treatment in chronic renal allograft rejection in the rat. Effect on structure and function. Transplantation 62 (1996) 1634-1642
    • (1996) Transplantation , vol.62 , pp. 1634-1642
    • Benediktsson, H.1    Chea, R.2    Davidoff, A.3    Paul, L.4
  • 35
    • 21744448809 scopus 로고    scopus 로고
    • Blood pressure control, drug therapy, and kidney disease
    • for the African American Study of Kidney Disease and Hypertension Study Group Investigators
    • Contreras G., Greene T., Agodoa L., et al., for the African American Study of Kidney Disease and Hypertension Study Group Investigators. Blood pressure control, drug therapy, and kidney disease. Hypertension 46 (2005) 44-50
    • (2005) Hypertension , vol.46 , pp. 44-50
    • Contreras, G.1    Greene, T.2    Agodoa, L.3
  • 36
    • 0038155497 scopus 로고    scopus 로고
    • Effects of blood pressure level on progression of diabetic nephropathy: Results from the RENAAL study
    • for the RENAAL Study Group
    • Bakris G., Weir M., Shanifar S., et al., for the RENAAL Study Group. Effects of blood pressure level on progression of diabetic nephropathy: Results from the RENAAL study. Arch Intern Med 163 (2003) 1555-1565
    • (2003) Arch Intern Med , vol.163 , pp. 1555-1565
    • Bakris, G.1    Weir, M.2    Shanifar, S.3
  • 37
    • 15844414184 scopus 로고    scopus 로고
    • Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): Multicentre, randomised controlled trial
    • for the REIN-2 Study Group
    • Ruggenenti P., Perna A., Loriga G., et al., for the REIN-2 Study Group. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): Multicentre, randomised controlled trial. Lancet 365 (2005) 939-946
    • (2005) Lancet , vol.365 , pp. 939-946
    • Ruggenenti, P.1    Perna, A.2    Loriga, G.3
  • 38
    • 2442703942 scopus 로고    scopus 로고
    • Differential effects of calcium antagonist subclasses on markers of nephropathy progression
    • Bakris G., Weir M., Secic M., et al. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int 65 (2004) 1991-2002
    • (2004) Kidney Int , vol.65 , pp. 1991-2002
    • Bakris, G.1    Weir, M.2    Secic, M.3
  • 39
    • 0030943496 scopus 로고    scopus 로고
    • Proteinuria in mild to moderate hypertension: Results of the VA cooperative study of six antihypertensive agents and placebo
    • for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents
    • Preston R., Materson B., Reda D., et al., for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Proteinuria in mild to moderate hypertension: Results of the VA cooperative study of six antihypertensive agents and placebo. Clin Nephrol 47 (1997) 310-315
    • (1997) Clin Nephrol , vol.47 , pp. 310-315
    • Preston, R.1    Materson, B.2    Reda, D.3
  • 40
    • 0036528790 scopus 로고    scopus 로고
    • Dissociation between blood pressure reduction and fall in proteinuria in primary renal disease: A randomized double-blind trial
    • PROCOPA Study Group
    • PROCOPA Study Group. Dissociation between blood pressure reduction and fall in proteinuria in primary renal disease: A randomized double-blind trial. J Hypertens 20 (2002) 729-737
    • (2002) J Hypertens , vol.20 , pp. 729-737
  • 41
    • 7444221237 scopus 로고    scopus 로고
    • Preventing microalbuminuria in type 2 diabetes
    • for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators
    • Ruggenenti P., Fassi A., Ilieva A., et al., for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 351 (2004) 1941-1951
    • (2004) N Engl J Med , vol.351 , pp. 1941-1951
    • Ruggenenti, P.1    Fassi, A.2    Ilieva, A.3
  • 42
    • 0035715175 scopus 로고    scopus 로고
    • Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model
    • Griffin K., Picken M., Bakris G., and Bidani A. Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model. Hypertension 37 (2001) 1268-1272
    • (2001) Hypertension , vol.37 , pp. 1268-1272
    • Griffin, K.1    Picken, M.2    Bakris, G.3    Bidani, A.4
  • 43
    • 4344633901 scopus 로고    scopus 로고
    • Calcium channel blockers, either amlodipine or mibefradil, ameliorate renal injury in experimental diabetes
    • Ma G., Allen T., Cooper M., and Cao Z. Calcium channel blockers, either amlodipine or mibefradil, ameliorate renal injury in experimental diabetes. Kidney Int 66 (2004) 1090-1098
    • (2004) Kidney Int , vol.66 , pp. 1090-1098
    • Ma, G.1    Allen, T.2    Cooper, M.3    Cao, Z.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.