메뉴 건너뛰기




Volumn 33, Issue 8, 2010, Pages 1027-1035

Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT

Author keywords

Adenosine; Dopamine; EEG spectral analysis; Pharmacogenetics; Sleep deprivation

Indexed keywords

CAFFEINE; CATECHOL METHYLTRANSFERASE; METHIONINE; MODAFINIL; PLACEBO; VALINE; BENZHYDRYL DERIVATIVE; CENTRAL STIMULANT AGENT;

EID: 77955616579     PISSN: 01618105     EISSN: 15509109     Source Type: Journal    
DOI: 10.1093/sleep/33.8.1027     Document Type: Article
Times cited : (37)

References (53)
  • 1
    • 0020368354 scopus 로고
    • A two process model of sleep regulation
    • Borbély AA. A two process model of sleep regulation. Hum Neurobiol 1982;1:195-204.
    • (1982) Hum Neurobiol , vol.1 , pp. 195-204
    • Borbély, A.A.1
  • 2
    • 47249106395 scopus 로고    scopus 로고
    • Sleep deprivation and vigilant attention
    • Lim JL, Dinges DF. Sleep deprivation and vigilant attention. Ann N Y Acad Sci 2008;1129:305-22.
    • (2008) Ann N Y Acad Sci , vol.1129 , pp. 305-322
    • Lim, J.L.1    Dinges, D.F.2
  • 3
    • 67649909704 scopus 로고    scopus 로고
    • Neurocognitive consequences of sleep deprivation
    • Goel N, Rao H, Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol 2009;29:320-39.
    • (2009) Semin Neurol , vol.29 , pp. 320-339
    • Goel, N.1    Rao, H.2    Durmer, J.S.3    Dinges, D.F.4
  • 4
    • 84882913064 scopus 로고    scopus 로고
    • Sleep homeostasis and models of sleep regulation
    • Kryger MH, Roth T, Dement WC, eds. 4th ed. Philadelphia, PA: Elsevier Saunders
    • Borbély AA, Achermann P. Sleep homeostasis and models of sleep regulation. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 4th ed. Philadelphia, PA: Elsevier Saunders, 2005:405-17.
    • (2005) Principles and Practice of Sleep Medicine , pp. 405-417
    • Borbély, A.A.1    Achermann, P.2
  • 6
    • 0034669115 scopus 로고    scopus 로고
    • Dual electroencephalogram markers of human sleep homeostasis: Correlation between theta activity in waking and slow-wave activity in sleep
    • Finelli LA, Baumann H, Borbély AA, Achermann P. Dual electroencephalogram markers of human sleep homeostasis: correlation between theta activity in waking and slow-wave activity in sleep. Neuroscience 2000;101:523-9.
    • (2000) Neuroscience , vol.101 , pp. 523-529
    • Finelli, L.A.1    Baumann, H.2    Borbély, A.A.3    Achermann, P.4
  • 7
    • 5044226800 scopus 로고    scopus 로고
    • Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans
    • Landolt HP, Rétey JV, Tönz K, et al. Caffeine attenuates waking and sleep electroencephalographic markers of sleep homeostasis in humans. Neuropsychopharmacology 2004;29:1933-9.
    • (2004) Neuropsychopharmacology , vol.29 , pp. 1933-1939
    • Landolt, H.P.1    Rétey, J.V.2    Tönz, K.3
  • 8
    • 33749853623 scopus 로고    scopus 로고
    • Adenosinergic mechanisms contribute to individual differences in sleep-deprivation induced changes in neurobehavioral function and brain rhythmic activity
    • Rétey JV, Adam M, Gottselig JM, et al. Adenosinergic mechanisms contribute to individual differences in sleep-deprivation induced changes in neurobehavioral function and brain rhythmic activity. J Neurosci 2006;26:10472-9.
    • (2006) J Neurosci , vol.26 , pp. 10472-10479
    • Rétey, J.V.1    Adam, M.2    Gottselig, J.M.3
  • 9
    • 65449131283 scopus 로고    scopus 로고
    • Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area
    • Schmidt C, Collette F, Leclercq Y, et al. Homeostatic sleep pressure and responses to sustained attention in the suprachiasmatic area. Science 2009;324:516-9.
    • (2009) Science , vol.324 , pp. 516-519
    • Schmidt, C.1    Collette, F.2    Leclercq, Y.3
  • 10
    • 1442304804 scopus 로고    scopus 로고
    • Dealing with inter-individual differences in the temporal dynamics of fatigue and performance: Importance and techniques
    • Van Dongen HPA, Maislin G, Dinges DF. Dealing with inter-individual differences in the temporal dynamics of fatigue and performance: Importance and techniques. Aviat Space Environ Med 2004;75:A147-a54.
    • (2004) Aviat Space Environ Med , vol.75
    • Van Dongen, H.P.A.1    Maislin, G.2    Dinges, D.F.3
  • 11
    • 39049124253 scopus 로고    scopus 로고
    • Sharp and sleepy: Evidence for dissociation between sleep pressure and nocturnal performance
    • Galliaud E, Taillard J, Sagaspei P, Valtati C, Bioulac B, Philip P. Sharp and sleepy: evidence for dissociation between sleep pressure and nocturnal performance. J Sleep Res 2008;17:11-5.
    • (2008) J Sleep Res , vol.17 , pp. 11-15
    • Galliaud, E.1    Taillard, J.2    Sagaspei, P.3    Valtati, C.4    Bioulac, B.5    Philip, P.6
  • 12
    • 39049110674 scopus 로고    scopus 로고
    • Relationships between affect, vigilance, and sleepiness following sleep deprivation
    • Franzen PL, Siegle GJ, Buysse DJ. Relationships between affect, vigilance, and sleepiness following sleep deprivation. J Sleep Res 2008;17:34-41.
    • (2008) J Sleep Res , vol.17 , pp. 34-41
    • Franzen, P.L.1    Siegle, G.J.2    Buysse, D.J.3
  • 13
    • 47349091349 scopus 로고    scopus 로고
    • Sleepiness and performance in response to repeated sleep restriction and subsequent recovery during semi-laboratory conditions
    • Axelsson J, Kecklund G, Akerstedt T, Donofrio P, Lekander M, Ingre M. Sleepiness and performance in response to repeated sleep restriction and subsequent recovery during semi-laboratory conditions. Chronobiol Int 2008;25:297-308.
    • (2008) Chronobiol Int , vol.25 , pp. 297-308
    • Axelsson, J.1    Kecklund, G.2    Akerstedt, T.3    Donofrio, P.4    Lekander, M.5    Ingre, M.6
  • 14
    • 60349109326 scopus 로고    scopus 로고
    • Pharmacogenetics of modafinil after sleep loss: Catechol-o- methyltransferase genotype modulates waking functions but not recovery sleep
    • Bodenmann S, Xu S, Luhmann UFO, et al. Pharmacogenetics of modafinil after sleep loss: catechol-o-methyltransferase genotype modulates waking functions but not recovery sleep. Clin Pharmacol Ther 2009;85:296-304.
    • (2009) Clin Pharmacol Ther , vol.85 , pp. 296-304
    • Bodenmann, S.1    Xu, S.2    Luhmann, U.F.O.3
  • 15
    • 24644435842 scopus 로고    scopus 로고
    • The use of stimulants to modify performance during sleep loss: A review by the sleep deprivation and Stimulant Task Force of the American Academy of Sleep Medicine
    • Bonnet MH, Balkin TJ, Dinges DF, et al. The use of stimulants to modify performance during sleep loss: a review by the sleep deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep 2005;28:1163-87.
    • (2005) Sleep , vol.28 , pp. 1163-1187
    • Bonnet, M.H.1    Balkin, T.J.2    Dinges, D.F.3
  • 16
    • 43049139109 scopus 로고    scopus 로고
    • Sleep homeostasis: A role for adenosine in humans?
    • Landolt HP. Sleep homeostasis: A role for adenosine in humans? Biochem Pharmacol 2008;75:2070-9.
    • (2008) Biochem Pharmacol , vol.75 , pp. 2070-2079
    • Landolt, H.P.1
  • 18
    • 0028964084 scopus 로고
    • Caffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night
    • Landolt HP, Werth E, Borbély AA, Dijk DJ. Caffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night. Brain Research 1995;675:67-74.
    • (1995) Brain Research , vol.675 , pp. 67-74
    • Landolt, H.P.1    Werth, E.2    Borbély, A.A.3    Dijk, D.J.4
  • 19
    • 0029658934 scopus 로고    scopus 로고
    • 6-cyclopentyladenosine and caffeine on sleep regulation in the rat
    • 6-cyclopentyladenosine and caffeine on sleep regulation in the rat. Eur J Pharmacol 1996;300:163-71.
    • (1996) Eur J Pharmacol , vol.300 , pp. 163-171
    • Schwierin, B.1    Borbély, A.A.2    Tobler, I.3
  • 20
    • 33646773600 scopus 로고    scopus 로고
    • Challenging sleep in aging: The effects of 200 mg of caffeine during the evening in young and middle-aged moderate caffeine consumers
    • Drapeau C, Hamel-Hébert I, Robillard R, Selmaoui B, Filipini D, Carrier J. Challenging sleep in aging: the effects of 200 mg of caffeine during the evening in young and middle-aged moderate caffeine consumers. J Sleep Res 2006;15:133-41.
    • (2006) J Sleep Res , vol.15 , pp. 133-141
    • Drapeau, C.1    Hamel-Hébert, I.2    Robillard, R.3    Selmaoui, B.4    Filipini, D.5    Carrier, J.6
  • 21
    • 34247271988 scopus 로고    scopus 로고
    • 2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep
    • 2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. Clin Pharmacol Ther 2007;81:692-8.
    • (2007) Clin Pharmacol Ther , vol.81 , pp. 692-698
    • Rétey, J.V.1    Adam, M.2    Khatami, R.3
  • 22
    • 27344454837 scopus 로고    scopus 로고
    • A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans
    • Rétey JV, Adam M, Honegger E, et al. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A 2005;102:15676-81.
    • (2005) Proc Natl Acad Sci U S A , vol.102 , pp. 15676-15681
    • Rétey, J.V.1    Adam, M.2    Honegger, E.3
  • 23
    • 33745738094 scopus 로고    scopus 로고
    • Effects of modafinil on cognitive performance and alertness during sleep deprivation
    • Wesensten NJ. Effects of modafinil on cognitive performance and alertness during sleep deprivation. Curr Pharm Des 2006;12:2457-71.
    • (2006) Curr Pharm des , vol.12 , pp. 2457-2471
    • Wesensten, N.J.1
  • 25
    • 43649090464 scopus 로고    scopus 로고
    • Modafinil: A review of neurochemical actions and effects on cognition
    • Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 2008;33:1477-502.
    • (2008) Neuropsychopharmacology , vol.33 , pp. 1477-1502
    • Minzenberg, M.J.1    Carter, C.S.2
  • 27
    • 51649122289 scopus 로고    scopus 로고
    • Dopaminergic D-1 and D-2 receptors are essential for the arousal effect of modafinil
    • Qu WM, Huang ZL, Xu XH, Matsumoto N, Urade Y. Dopaminergic D-1 and D-2 receptors are essential for the arousal effect of modafinil. J Neurosci 2008;28:8462-9.
    • (2008) J Neurosci , vol.28 , pp. 8462-8469
    • Qu, W.M.1    Huang, Z.L.2    Xu, X.H.3    Matsumoto, N.4    Urade, Y.5
  • 28
    • 62649136134 scopus 로고    scopus 로고
    • Effects of modafinil on dopamine and dopamine transporters in the male human brain: Clinical implications
    • Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA 2009;301:1148-54.
    • (2009) JAMA , vol.301 , pp. 1148-1154
    • Volkow, N.D.1    Fowler, J.S.2    Logan, J.3
  • 29
    • 69749112915 scopus 로고    scopus 로고
    • The functional Val158Met polymorphism of COMT predicts interindividual differences in brain alpha oscillations in young men
    • Bodenmann S, Rusterholz T, Durr R, et al. The functional Val158Met polymorphism of COMT predicts interindividual differences in brain alpha oscillations in young men. J Neurosci 2009;29:10855-62.
    • (2009) J Neurosci , vol.29 , pp. 10855-10862
    • Bodenmann, S.1    Rusterholz, T.2    Durr, R.3
  • 32
    • 0029565905 scopus 로고
    • Power density in theta/alpha frequencies of the waking EEG progressively increases during sustained wakefulness
    • Cajochen C, Brunner DP, Kräuchi K, Graw P, Wirz-Justice A. Power density in theta/alpha frequencies of the waking EEG progressively increases during sustained wakefulness. Sleep 1995;18:890-4.
    • (1995) Sleep , vol.18 , pp. 890-894
    • Cajochen, C.1    Brunner, D.P.2    Kräuchi, K.3    Graw, P.4    Wirz-Justice, A.5
  • 33
    • 6344265879 scopus 로고    scopus 로고
    • Functional analysis of genetic variation in catechol-o-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain
    • Chen JS, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-o-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 2004;75:807-21.
    • (2004) Am J Hum Genet , vol.75 , pp. 807-821
    • Chen, J.S.1    Lipska, B.K.2    Halim, N.3
  • 34
    • 0030004521 scopus 로고    scopus 로고
    • Human catechol-O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders
    • Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996;6:243-50.
    • (1996) Pharmacogenetics , vol.6 , pp. 243-250
    • Lachman, H.M.1    Papolos, D.F.2    Saito, T.3    Yu, Y.M.4    Szumlanski, C.L.5    Weinshilboum, R.M.6
  • 35
    • 47749122607 scopus 로고    scopus 로고
    • COMT genotype predicts cortical-limbic D1 receptor availability measured with [C-11]NNC112 and PET
    • Slifstein M, Kolachana B, Simpson EH, et al. COMT genotype predicts cortical-limbic D1 receptor availability measured with [C-11]NNC112 and PET. Mol Psychiatry 2008;13:821-7.
    • (2008) Mol Psychiatry , vol.13 , pp. 821-827
    • Slifstein, M.1    Kolachana, B.2    Simpson, E.H.3
  • 36
    • 60349116939 scopus 로고    scopus 로고
    • Impact of interacting functional variants in COMT on regional gray matter volume in human brain
    • Honea R, Verchinski BA, Pezawas L, et al. Impact of interacting functional variants in COMT on regional gray matter volume in human brain. Neuroimage 2009;45:44-51.
    • (2009) Neuroimage , vol.45 , pp. 44-51
    • Honea, R.1    Verchinski, B.A.2    Pezawas, L.3
  • 37
    • 51649131485 scopus 로고    scopus 로고
    • Sleep deprivation decreases binding of [C-11]raclopride to dopamine D-2/D-3 receptors in the human brain
    • Volkow ND, Wang GJ, Telang F, et al. Sleep deprivation decreases binding of [C-11]raclopride to dopamine D-2/D-3 receptors in the human brain. J Neurosci 2008;28:8454-61.
    • (2008) J Neurosci , vol.28 , pp. 8454-8461
    • Volkow, N.D.1    Wang, G.J.2    Telang, F.3
  • 38
    • 62049086105 scopus 로고    scopus 로고
    • Hyperstimulation of striatal D2 receptors with sleep deprivation: Implications for cognitive impairment
    • Volkow ND, Tomasi D, Wang GJ, et al. Hyperstimulation of striatal D2 receptors with sleep deprivation: Implications for cognitive impairment. Neuroimage 2009;45:1232-40.
    • (2009) Neuroimage , vol.45 , pp. 1232-1240
    • Volkow, N.D.1    Tomasi, D.2    Wang, G.J.3
  • 39
    • 4944236929 scopus 로고    scopus 로고
    • What keeps us awake: The neuropharmacology of stimulants and wakefulness promoting medications
    • Boutrel B, Koob GF. What keeps us awake: The neuropharmacology of stimulants and wakefulness promoting medications. Sleep 2004;27:1181-94.
    • (2004) Sleep , vol.27 , pp. 1181-1194
    • Boutrel, B.1    Koob, G.F.2
  • 40
    • 0034072996 scopus 로고    scopus 로고
    • Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat
    • Lin JS, Gervasoni D, Hou Y, et al. Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat. J Sleep Res 2000;9:89-96.
    • (2000) J Sleep Res , vol.9 , pp. 89-96
    • Lin, J.S.1    Gervasoni, D.2    Hou, Y.3
  • 41
    • 0028898073 scopus 로고
    • Awakening properties of modafinil without paradoxical sleep rebound: Comparative study with amphetamine in the rat
    • Touret M, Sallanon-Moulin M, Jouvet M. Awakening properties of modafinil without paradoxical sleep rebound: Comparative study with amphetamine in the rat. Neurosci Lett 1995;189:43-6.
    • (1995) Neurosci Lett , vol.189 , pp. 43-46
    • Touret, M.1    Sallanon-Moulin, M.2    Jouvet, M.3
  • 42
    • 33947161911 scopus 로고    scopus 로고
    • The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders
    • Parmentier R, Anaclet C, Guhennec C, et al. The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochem Pharmacol 2007;73:1157-71.
    • (2007) Biochem Pharmacol , vol.73 , pp. 1157-1171
    • Parmentier, R.1    Anaclet, C.2    Guhennec, C.3
  • 43
    • 0029565951 scopus 로고
    • Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep
    • Buguet A, Montmayeur A, Pigeau R, Naitoh P. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep. J Sleep Res 1995;4:229-41.
    • (1995) J Sleep Res , vol.4 , pp. 229-241
    • Buguet, A.1    Montmayeur, A.2    Pigeau, R.3    Naitoh, P.4
  • 45
    • 0030775911 scopus 로고    scopus 로고
    • Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat
    • Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther 1997;283:757-69.
    • (1997) J Pharmacol Exp Ther , vol.283 , pp. 757-769
    • Edgar, D.M.1    Seidel, W.F.2
  • 46
    • 0036629760 scopus 로고    scopus 로고
    • Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice
    • Kopp C, Petit JM, Magistretti P, Borbely AA, Tobler I. Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice. Neuropharmacology 2002;43:110-8.
    • (2002) Neuropharmacology , vol.43 , pp. 110-118
    • Kopp, C.1    Petit, J.M.2    Magistretti, P.3    Borbely, A.A.4    Tobler, I.5
  • 47
    • 0024328831 scopus 로고
    • Differential-effects of a new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behavior in young healthy-volunteers
    • Saletu B, Frey R, Krupka M, Anderer P, Grunberger J, Barbanoj MJ. Differential-effects of a new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behavior in young healthy-volunteers. Int J Clin Pharmacol Res 1989;9:183-95.
    • (1989) Int J Clin Pharmacol Res , vol.9 , pp. 183-195
    • Saletu, B.1    Frey, R.2    Krupka, M.3    Anderer, P.4    Grunberger, J.5    Barbanoj, M.J.6
  • 48
    • 24644483838 scopus 로고    scopus 로고
    • Performance and alertness effects of caffeine, dextro amphetamine, and modafinil during sleep deprivation
    • Wesensten NJ, Killgore WDS, Balkin TJ. Performance and alertness effects of caffeine, dextro amphetamine, and modafinil during sleep deprivation. J Sleep Res 2005;14:255-66.
    • (2005) J Sleep Res , vol.14 , pp. 255-266
    • Wesensten, N.J.1    Killgore, W.D.S.2    Balkin, T.J.3
  • 49
    • 85036753980 scopus 로고    scopus 로고
    • Effects of a single dose of modafinil on EEG during the MWT during acute sleep deprivation
    • James LM, Dijk D, Boyle J, et al. Effects of a single dose of modafinil on EEG during the MWT during acute sleep deprivation. J Sleep Res 2008;17:206-.
    • (2008) J Sleep Res , vol.17 , pp. 206
    • James, L.M.1    Dijk, D.2    Boyle, J.3
  • 50
    • 0344193511 scopus 로고    scopus 로고
    • Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG
    • Chapotot F, Pigeau R, Canini F, Bourdon L, Buguet A. Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG. Psychopharmacology 2003;166:127-38.
    • (2003) Psychopharmacology , vol.166 , pp. 127-138
    • Chapotot, F.1    Pigeau, R.2    Canini, F.3    Bourdon, L.4    Buguet, A.5
  • 51
    • 0027368618 scopus 로고
    • Dynamics of electroencephalographic sleep spindles and slow wave activity in men: Effect of sleep deprivation
    • Dijk DJ, Hayes B, Czeisler CA. Dynamics of electroencephalographic sleep spindles and slow wave activity in men: effect of sleep deprivation. Brain Res 1993;626:190-9.
    • (1993) Brain Res , vol.626 , pp. 190-199
    • Dijk, D.J.1    Hayes, B.2    Czeisler, C.A.3
  • 52
    • 0030066645 scopus 로고    scopus 로고
    • Homeostatic sleep regulation in habitual short sleepers and long sleepers
    • Aeschbach D, Cajochen C, Landolt HP, Borbély AA. Homeostatic sleep regulation in habitual short sleepers and long sleepers. Am J Physiol 1996;270:R41-R53.
    • (1996) Am J Physiol , vol.270
    • Aeschbach, D.1    Cajochen, C.2    Landolt, H.P.3    Borbély, A.A.4
  • 53
    • 0036179047 scopus 로고    scopus 로고
    • Pergolide restores sleep maintenance but impairs slee EEG synchronization in patients with restless legs syndrome
    • Tagaya H, Wetter TC, Winkelmann J, et al. Pergolide restores sleep maintenance but impairs slee EEG synchronization in patients with restless legs syndrome. Sleep Med 2002;3:49-54.
    • (2002) Sleep Med , vol.3 , pp. 49-54
    • Tagaya, H.1    Wetter, T.C.2    Winkelmann, J.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.