메뉴 건너뛰기




Volumn 26, Issue 1, 2007, Pages 119-127

Antibody induction by virosomal, MF59-adjuvanted, or conventional influenza vaccines in the elderly

Author keywords

Adjuvant; Elderly; Influenza; Subunit; Vaccine; Virosome

Indexed keywords

HEMAGGLUTININ; INFLUENZA VACCINE; N ACETYLMURAMYLALANYL DEXTRO ISOGLUTAMINYLALANYL DIPALMITOYLPHOSPHATIDYLETHANOLAMINE; TRIPLE VACCINE; VIROSOME VACCINE;

EID: 36749096389     PISSN: 0264410X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.vaccine.2007.10.051     Document Type: Article
Times cited : (54)

References (53)
  • 2
    • 22544459957 scopus 로고    scopus 로고
    • The unmet need in the elderly: designing new influenza vaccines for older adults
    • McElhaney J.E. The unmet need in the elderly: designing new influenza vaccines for older adults. Vaccine 23 Suppl 1 (2005) S10-S25
    • (2005) Vaccine , vol.23 , Issue.SUPPL. 1
    • McElhaney, J.E.1
  • 3
    • 0027336290 scopus 로고
    • Impact of influenza on mortality in relation to age and underlying disease, 1967-1989
    • Sprenger M.J.W., Mulder P.G.H., Beyer W.E.P., van Strik R., and Masurel N. Impact of influenza on mortality in relation to age and underlying disease, 1967-1989. Int J Epidem 22 2 (1993) 334-340
    • (1993) Int J Epidem , vol.22 , Issue.2 , pp. 334-340
    • Sprenger, M.J.W.1    Mulder, P.G.H.2    Beyer, W.E.P.3    van Strik, R.4    Masurel, N.5
  • 4
    • 0020035742 scopus 로고
    • Pneumonia and influenza death during epidemics/implications for prevention
    • Barker W.H., and Mullooly J.P. Pneumonia and influenza death during epidemics/implications for prevention. Arch Intern Med 142 1 (1982) 85-89
    • (1982) Arch Intern Med , vol.142 , Issue.1 , pp. 85-89
    • Barker, W.H.1    Mullooly, J.P.2
  • 5
    • 0020334815 scopus 로고
    • Serious morbidity and mortality associated with influenza epidemics
    • Glezen W.P. Serious morbidity and mortality associated with influenza epidemics. Epidemiol Rev 4 1 (1982) 25-44
    • (1982) Epidemiol Rev , vol.4 , Issue.1 , pp. 25-44
    • Glezen, W.P.1
  • 7
    • 22544470916 scopus 로고    scopus 로고
    • The impact of influenza on the health and health care utilisation of elderly people
    • Fleming D.M., and Elliot A.J. The impact of influenza on the health and health care utilisation of elderly people. Vaccine 23 Suppl 1 (2005) S1-S9
    • (2005) Vaccine , vol.23 , Issue.SUPPL. 1
    • Fleming, D.M.1    Elliot, A.J.2
  • 8
    • 0034072777 scopus 로고    scopus 로고
    • The impact of influenza epidemics on hospitalizations
    • Simonsen L., Fukuda K., Schonberger L.B., and Cox N.J. The impact of influenza epidemics on hospitalizations. J Infect Dis 181 3 (2000) 831-837
    • (2000) J Infect Dis , vol.181 , Issue.3 , pp. 831-837
    • Simonsen, L.1    Fukuda, K.2    Schonberger, L.B.3    Cox, N.J.4
  • 10
    • 0029128905 scopus 로고
    • The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature
    • Gross P.A., Hermogenes A.W., Sacks H.S., Lau J., and Levandowski R.A. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Ann Intern Med 123 7 (1995) 518-527
    • (1995) Ann Intern Med , vol.123 , Issue.7 , pp. 518-527
    • Gross, P.A.1    Hermogenes, A.W.2    Sacks, H.S.3    Lau, J.4    Levandowski, R.A.5
  • 11
    • 0032517071 scopus 로고    scopus 로고
    • Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens
    • Nichol K.L., Wuorenma J., and Von Sternberg T. Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med 158 16 (1998) 1769-1776
    • (1998) Arch Intern Med , vol.158 , Issue.16 , pp. 1769-1776
    • Nichol, K.L.1    Wuorenma, J.2    Von Sternberg, T.3
  • 12
    • 0033954496 scopus 로고    scopus 로고
    • Immunity to influenza in the elderly
    • Webster R.G. Immunity to influenza in the elderly. Vaccine 18 16 (2000) 1686-1689
    • (2000) Vaccine , vol.18 , Issue.16 , pp. 1686-1689
    • Webster, R.G.1
  • 13
    • 0037417219 scopus 로고    scopus 로고
    • Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly
    • Nichol K.L., Nordin J., Mullooly J., Lask R., Fillbrandt K., and Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 348 14 (2003) 1322-1332
    • (2003) N Engl J Med , vol.348 , Issue.14 , pp. 1322-1332
    • Nichol, K.L.1    Nordin, J.2    Mullooly, J.3    Lask, R.4    Fillbrandt, K.5    Iwane, M.6
  • 15
    • 29144456834 scopus 로고    scopus 로고
    • Influenza vaccination in elderly people
    • Simonsen L., Viboud C., and Taylor R. Influenza vaccination in elderly people. Lancet 366 9503 (2005) 2086
    • (2005) Lancet , vol.366 , Issue.9503 , pp. 2086
    • Simonsen, L.1    Viboud, C.2    Taylor, R.3
  • 16
    • 25844467829 scopus 로고    scopus 로고
    • Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review
    • Jefferson T., Rivetti D., Rivetti A., Rudin M., Di Pietrantonj C., and Demicheli V. Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review. Lancet 366 9492 (2005) 1165-1174
    • (2005) Lancet , vol.366 , Issue.9492 , pp. 1165-1174
    • Jefferson, T.1    Rivetti, D.2    Rivetti, A.3    Rudin, M.4    Di Pietrantonj, C.5    Demicheli, V.6
  • 17
    • 1842623500 scopus 로고    scopus 로고
    • Influenza vaccines
    • WHO. Influenza vaccines. Weekly Epidem Rec 77 8 (2002) 229-240
    • (2002) Weekly Epidem Rec , vol.77 , Issue.8 , pp. 229-240
    • WHO1
  • 18
    • 0033015825 scopus 로고    scopus 로고
    • Influenza vaccination in elderly people
    • Remarque E.J. Influenza vaccination in elderly people. Exp Gerontol 34 3 (1999) 445-452
    • (1999) Exp Gerontol , vol.34 , Issue.3 , pp. 445-452
    • Remarque, E.J.1
  • 19
    • 32044453088 scopus 로고    scopus 로고
    • Antibody response to influenza vaccination in the elderly: a quantitative review
    • Goodwin K., Viboud C., and Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24 8 (2006) 1159-1169
    • (2006) Vaccine , vol.24 , Issue.8 , pp. 1159-1169
    • Goodwin, K.1    Viboud, C.2    Simonsen, L.3
  • 20
    • 0035202615 scopus 로고    scopus 로고
    • Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals
    • Goronzy J.J., Fulbright J.W., Crowson C.S., Poland G.A., O'Fallon W.M., and Weyand C.M. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75 24 (2001) 12182
    • (2001) J Virol , vol.75 , Issue.24 , pp. 12182
    • Goronzy, J.J.1    Fulbright, J.W.2    Crowson, C.S.3    Poland, G.A.4    O'Fallon, W.M.5    Weyand, C.M.6
  • 21
    • 0037012001 scopus 로고    scopus 로고
    • Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly
    • Murasko D.M., Bernstein E.D., Gardner E.M., Gross P., Munk G., Dran S., et al. Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly. Exp. Gerontol. 37 2-3 (2002) 427-439
    • (2002) Exp. Gerontol. , vol.37 , Issue.2-3 , pp. 427-439
    • Murasko, D.M.1    Bernstein, E.D.2    Gardner, E.M.3    Gross, P.4    Munk, G.5    Dran, S.6
  • 22
    • 0037403081 scopus 로고    scopus 로고
    • Novel generations of influenza vaccines
    • Kemble G., and Greenberg H. Novel generations of influenza vaccines. Vaccine 21 16 (2003) 1789-1795
    • (2003) Vaccine , vol.21 , Issue.16 , pp. 1789-1795
    • Kemble, G.1    Greenberg, H.2
  • 23
    • 0030266157 scopus 로고    scopus 로고
    • A virosome vaccine antigen delivery system does not stimulate an antiphospholipid antibody response in humans
    • Cryz S.J., Que J.U., and Gluck R. A virosome vaccine antigen delivery system does not stimulate an antiphospholipid antibody response in humans. Vaccine 14 14 (1996) 1381-1383
    • (1996) Vaccine , vol.14 , Issue.14 , pp. 1381-1383
    • Cryz, S.J.1    Que, J.U.2    Gluck, R.3
  • 24
    • 0037435832 scopus 로고    scopus 로고
    • Influenza virosomes: combining optimal presentation of hemagglutinin with immunopotentiating activity
    • Huckriede A., Bungener L., ter Veer W., Holtrop M., Daemen T., Palache A.M., et al. Influenza virosomes: combining optimal presentation of hemagglutinin with immunopotentiating activity. Vaccine 21 9-10 (2003) 925-931
    • (2003) Vaccine , vol.21 , Issue.9-10 , pp. 925-931
    • Huckriede, A.1    Bungener, L.2    ter Veer, W.3    Holtrop, M.4    Daemen, T.5    Palache, A.M.6
  • 26
    • 12344265748 scopus 로고    scopus 로고
    • Virosome-mediated delivery of protein antigens in vivo: efficient induction of class I MHC-restricted cytotoxic T lymphocyte activity
    • Bungener L., Huckriede A., de Mare A., Vries-Idema J., Wilschut J., and Daemen T. Virosome-mediated delivery of protein antigens in vivo: efficient induction of class I MHC-restricted cytotoxic T lymphocyte activity. Vaccine 23 10 (2005) 1232-1241
    • (2005) Vaccine , vol.23 , Issue.10 , pp. 1232-1241
    • Bungener, L.1    Huckriede, A.2    de Mare, A.3    Vries-Idema, J.4    Wilschut, J.5    Daemen, T.6
  • 27
    • 0027984259 scopus 로고
    • Systemic cytokine profiles in BALB/c mice immunized with trivalent influenza vaccine containing MF59 oil emulsion and other advanced adjuvants
    • Valensi J.P.M., Carlson J.R., and van Nest G.A. Systemic cytokine profiles in BALB/c mice immunized with trivalent influenza vaccine containing MF59 oil emulsion and other advanced adjuvants. J Immunol 153 9 (1994) 4029-4039
    • (1994) J Immunol , vol.153 , Issue.9 , pp. 4029-4039
    • Valensi, J.P.M.1    Carlson, J.R.2    van Nest, G.A.3
  • 28
    • 0032889660 scopus 로고    scopus 로고
    • Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons
    • Minutello M., Senatore F., Cecchinelli G., Bianchi M., Andreani T., Podda A., et al. Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine 17 2 (1999) 99-104
    • (1999) Vaccine , vol.17 , Issue.2 , pp. 99-104
    • Minutello, M.1    Senatore, F.2    Cecchinelli, G.3    Bianchi, M.4    Andreani, T.5    Podda, A.6
  • 29
    • 0033529516 scopus 로고    scopus 로고
    • Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly
    • De Donato S., Granoff D., Minutello M., Lecchi G., Faccini M., Agnello M., et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine 17 23-24 (1999) 3094-3101
    • (1999) Vaccine , vol.17 , Issue.23-24 , pp. 3094-3101
    • De Donato, S.1    Granoff, D.2    Minutello, M.3    Lecchi, G.4    Faccini, M.5    Agnello, M.6
  • 30
    • 0035925666 scopus 로고    scopus 로고
    • The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine
    • Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine 19 17-19 (2001) 2673-2680
    • (2001) Vaccine , vol.19 , Issue.17-19 , pp. 2673-2680
    • Podda, A.1
  • 31
    • 0035858115 scopus 로고    scopus 로고
    • Comparison of three different influenza vaccines in institutionalised elderly
    • Baldo V., Menegon T., Bonello C., Floreani A., Trivello R., and Collaborative G. Comparison of three different influenza vaccines in institutionalised elderly. Vaccine 19 25-26 (2001) 3472-3475
    • (2001) Vaccine , vol.19 , Issue.25-26 , pp. 3472-3475
    • Baldo, V.1    Menegon, T.2    Bonello, C.3    Floreani, A.4    Trivello, R.5    Collaborative, G.6
  • 32
    • 0034801645 scopus 로고    scopus 로고
    • Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects
    • Gasparini R., Pozzi T., Montomoli E., Fragapane E., Senatore F., Minutello M., et al. Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects. Eur J Epidemiol 17 2 (2001) 135-140
    • (2001) Eur J Epidemiol , vol.17 , Issue.2 , pp. 135-140
    • Gasparini, R.1    Pozzi, T.2    Montomoli, E.3    Fragapane, E.4    Senatore, F.5    Minutello, M.6
  • 33
    • 0037261994 scopus 로고    scopus 로고
    • A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis
    • Banzhoff A., Nacci P., and Podda A. A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis. Gerontology 49 3 (2003) 177-184
    • (2003) Gerontology , vol.49 , Issue.3 , pp. 177-184
    • Banzhoff, A.1    Nacci, P.2    Podda, A.3
  • 34
    • 0035077630 scopus 로고    scopus 로고
    • Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly
    • Pregliasco F., Mensi C., Serpilli W., Speccher L., Masella P., and Belloni A. Immunogenicity and safety of three commercial influenza vaccines in institutionalized elderly. Aging (Milano) 13 1 (2001) 38-43
    • (2001) Aging (Milano) , vol.13 , Issue.1 , pp. 38-43
    • Pregliasco, F.1    Mensi, C.2    Serpilli, W.3    Speccher, L.4    Masella, P.5    Belloni, A.6
  • 35
    • 0037424108 scopus 로고    scopus 로고
    • Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects
    • Squarcione S., Sgricia S., Biasio L.R., and Perinetti E. Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects. Vaccine 21 11-12 (2003) 1268-1274
    • (2003) Vaccine , vol.21 , Issue.11-12 , pp. 1268-1274
    • Squarcione, S.1    Sgricia, S.2    Biasio, L.R.3    Perinetti, E.4
  • 36
    • 4043130309 scopus 로고    scopus 로고
    • Open, randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an MF59-adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly
    • Ruf B.R., Colberg K., Frick M., and Preusche A. Open, randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an MF59-adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly. Infection 32 4 (2004) 191-198
    • (2004) Infection , vol.32 , Issue.4 , pp. 191-198
    • Ruf, B.R.1    Colberg, K.2    Frick, M.3    Preusche, A.4
  • 37
    • 13844274197 scopus 로고    scopus 로고
    • Recommanded composition of influenza virus vaccines for use in the 2005 influenza season
    • WHO. Recommanded composition of influenza virus vaccines for use in the 2005 influenza season. Weekly Epidem Rec 41 79 (2004) 369-376
    • (2004) Weekly Epidem Rec , vol.41 , Issue.79 , pp. 369-376
    • WHO1
  • 38
    • 36749000124 scopus 로고    scopus 로고
    • Palmer DF, Dowdle WR, Coleman MT, Schild GC. Advanced laboratory techniques for influenza diagnosis. U.S. Dept. Health Edu. Welfare, P.H.S. Atlanta; 1975; Part 2, Hemagglutination Inhibition Test. p. 25-62.
  • 39
    • 36749001764 scopus 로고    scopus 로고
    • http://www.meddramsso.com/MSSOWeb/index.htm. 2007. (GENERIC) Ref Type: Electronic Citation.
  • 40
    • 36749036808 scopus 로고    scopus 로고
    • European Medicines Evaluation Agency. Note for guidance on harmonisation of requirements for influenza vaccines. Doc.Ref.CPMP/BWP/214/96. 1997. (GENERIC) Ref Type: Generic.
  • 41
    • 0034881249 scopus 로고    scopus 로고
    • Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children
    • Zangwill K.M., Droge J., Mendelman P., Marcy S.M., Partridge S., Chiu C.Y., et al. Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children. Pediatr Infect Dis J 20 8 (2001) 740-746
    • (2001) Pediatr Infect Dis J , vol.20 , Issue.8 , pp. 740-746
    • Zangwill, K.M.1    Droge, J.2    Mendelman, P.3    Marcy, S.M.4    Partridge, S.5    Chiu, C.Y.6
  • 42
    • 0037424114 scopus 로고    scopus 로고
    • Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities
    • Nolan T., Lee M.S., Cordova J.M., Cho I., Walker R.E., August M.J., et al. Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities. Vaccine 21 11-12 (2003) 1224-1231
    • (2003) Vaccine , vol.21 , Issue.11-12 , pp. 1224-1231
    • Nolan, T.1    Lee, M.S.2    Cordova, J.M.3    Cho, I.4    Walker, R.E.5    August, M.J.6
  • 43
    • 36749049373 scopus 로고    scopus 로고
    • ICH guideline E9 (Statistical Principles for Clinical Trials). Note for Guidance on Statistical Principles for Clinical Trials. CPMP/ICH/363/96. 1998. (GENERIC) Ref Type: Generic.
  • 44
    • 36749026737 scopus 로고    scopus 로고
    • FDA. Guidance for Industry: Clinical Data Needed to Support the Licensure of Trivalent Inactivated Influenza Vaccines - draft guidance. US Federal Register 2006; 71 (47 (Docket No. 2006D-0083)): 12367.
  • 45
    • 33748936477 scopus 로고    scopus 로고
    • Effect of needle size on immunogenicity and reactogenicity of vaccines in infants: randomised controlled trial
    • Diggle L., Deeks J.J., and Pollard A.J. Effect of needle size on immunogenicity and reactogenicity of vaccines in infants: randomised controlled trial. BMJ 333 7568 (2006) 571
    • (2006) BMJ , vol.333 , Issue.7568 , pp. 571
    • Diggle, L.1    Deeks, J.J.2    Pollard, A.J.3
  • 46
    • 0029836716 scopus 로고    scopus 로고
    • Functionally distinct T cells in three compartments of the respiratory tract after influenza virus infection
    • Baumgarth N., and Kelso A. Functionally distinct T cells in three compartments of the respiratory tract after influenza virus infection. Eur J Immunol 26 (1996) 2189-2197
    • (1996) Eur J Immunol , vol.26 , pp. 2189-2197
    • Baumgarth, N.1    Kelso, A.2
  • 47
    • 0027941401 scopus 로고
    • Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection
    • Graham M.B., Braciale V.L., and Braciale T.J. Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med 180 4 (1994) 1273-1282
    • (1994) J Exp Med , vol.180 , Issue.4 , pp. 1273-1282
    • Graham, M.B.1    Braciale, V.L.2    Braciale, T.J.3
  • 48
    • 0345269791 scopus 로고    scopus 로고
    • Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virus-infected mice
    • Johnson B.J., Costelloe E.O., Fitzpatrick D.R., Haanen J.B., Schumacher T.N., Brown L.E., et al. Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virus-infected mice. Proc Natl Acad Sci USA 100 5 (2003) 2657-2662
    • (2003) Proc Natl Acad Sci USA , vol.100 , Issue.5 , pp. 2657-2662
    • Johnson, B.J.1    Costelloe, E.O.2    Fitzpatrick, D.R.3    Haanen, J.B.4    Schumacher, T.N.5    Brown, L.E.6
  • 49
    • 33646468500 scopus 로고    scopus 로고
    • T cell responses are better correlates of vaccine protection in the elderly
    • McElhaney J.E., Xie D., Hager W.D., Barry M.B., Wang Y., Kleppinger A., et al. T cell responses are better correlates of vaccine protection in the elderly. J Immunol 176 10 (2006) 6333-6339
    • (2006) J Immunol , vol.176 , Issue.10 , pp. 6333-6339
    • McElhaney, J.E.1    Xie, D.2    Hager, W.D.3    Barry, M.B.4    Wang, Y.5    Kleppinger, A.6
  • 50
  • 51
    • 0031171265 scopus 로고    scopus 로고
    • Development of an adjuvant to enhance the immune response to influenza vaccine in the elderly
    • Martin J.T. Development of an adjuvant to enhance the immune response to influenza vaccine in the elderly. Biologicals 25 2 (1997) 209-213
    • (1997) Biologicals , vol.25 , Issue.2 , pp. 209-213
    • Martin, J.T.1
  • 52
    • 22544452446 scopus 로고    scopus 로고
    • Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy
    • Iob A., Brianti G., Zamparo E., and Gallo T. Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy. Epidemiol Infect 133 4 (2005) 687-693
    • (2005) Epidemiol Infect , vol.133 , Issue.4 , pp. 687-693
    • Iob, A.1    Brianti, G.2    Zamparo, E.3    Gallo, T.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.