Pharmacogenetic insights into depression and antidepressant response: does sex matter?
It is known that the frequency of men and women suffering from stress-related neuropsychiatric disorders is all but proportionally distributed. Notably, women are far more susceptible than men to the precipitation of depressive symptomatology. Some studies attribute this sex-specific vulnerability to the pronounced genetic predisposition that women may present towards the development of depressive disorders. Furthermore, clinical evidence support the notion that antidepressant response is also characterized by sex-specific manifestations; women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Despite the fact that the contribution of the “genome” remains elusive when it comes to major depression, compelling evidence has recently emerged pointing to sexually dimorphic influences of certain polymorphisms in genes related to the pathophysiology of major depression and antidepressant response, such as the serotonin transporter (5-HTT), serotonin 1A (5HT1A) receptor, monoamine oxidase A (MAO-A) and others. Given that the ultimate goal of pharmacogenetics is to provide “tailor-made” pharmacotherapies based on the genetic constitution of an individual, the factor of “sex” needs to be carefully addressed in disorders that are characterized by sex-specific manifestations. The aim of the present article is to highlight the importance of sex differences in depression and in antidepressant pharmacoresponse by providing intriguing insights from the field of pharmacogenetics.
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gender; stress; polymorphism; women; pharmacogenomics; SSRI; genes; serotonin
The frequency of men and women suffering from stress-related neuropsychiatric disorders is all but proportionally distributed; women are far more susceptible than men to major depression, generalized anxiety disorder, acute and post-traumatic stress disorders [1-8]. Paradoxically, considerably less attention has been given to sex-differences in the presentation and features of depression and in response to antidepressant treatment . This is not unrelated to the fact that women were under-represented in clinical trials prior to 1993 . The aetiology behind sex differences is not entirely known, but involves genetic, hormonal, biochemical and social factors. For instance, in a sociocultural perspective it has been suggested that modern women experience a “role strain”, while in the context of living the “sandwich generation” they have to provide care to both their progeny and elders [11, 12]. Nowadays, elegant genomic research highlights the fact that the genetic constitution of an individual, the hormonal milieu and imminent life stressors are inter-connected in a triangular arch (Fig. (1)).
Pharmacogenetics investigates how genes influence responsiveness to drugs, both in terms of efficacy and adverse effects. The ultimate goal of this interdisciplinary scientific field is to provide “tailor-made” pharmacotherapy based on the genetic constitution of an individual. The advent of elegant genetic/genomic techniques has set the basis for personalized medicine in neuropsychiatric disorders, such as major depression. During the years, it became apparent that polymorphisms in several genes regulating pharmacokinetics and pharmacodynamics are implicated in both the course of the depressive episode and in the outcome of the antidepressant treatment .
A battery of evidence implicates abnormalities in monoaminergic systems (i.e. serotonergic, noradrenergic and dopaminergic) in the pathophysiology of major depression but recent data show that many other systems are also involved . For instance, depression is now commonly viewed as an impairment of neural plasticity with decreases in adult hippocampal neurogenesis, neurotrophic factors and dendritic complexity . Depression associated with postpartum and perimenopausal periods has also begun to be studied with regard to hormonal influences and the interaction of hormones with neurobiological systems. It is well known that there are significant fluctuations in sex hormones and major changes in the hypothalamic-pituitary-adrenal (HPA) axis during these periods; dysregulation of the HPA axis and disrupted hormonal levels have also been implicated in stress response and occurrence of depression .
Elegant investigations have utilized animal models to elucidate the underlying mechanisms of depression and to test hypotheses regarding the increased incidence of depression among women. In particular, stress-inducing paradigms have been used on animals to invoke behaviors that mimic depressive symptoms [18-25]. Importantly, preclinical research in animal models underlines the critical role of sex in the manifestation of sex-based neurochemical, neurobiological, physiological, behavioural, and immune responses to both the induction of depressive-like behavior, as well as to concomitant antidepressant treatment (for review see ).
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Genetic predisposition to the development of depressive disorders is thought to be more pronounced in women than in men since major life stressors appear to exert sex-specific detrimental effects; it has been postulated that major depression is approximately twice as frequent in the female population and presents a significantly higher heritability in women compared to men (49% versus 29% respectively) [27, 28]. As noted in a recent review by Vigod and Stewart (2009) the role of sex has only been scantly addressed in pharmacogenetic research, until very recently . Today, there is evidence that there may be a sex-differentiated influence of certain polymorphisms with respect to both the development of depressive symptomatology and to the effectiveness of antidepressant response.
Aim & Method
In the present review we focus on positive findings regarding associations between variations in genes regulating pharmacokinetics and pharmacodynamics that have been reported to affect antidepressant response and depressive symptomatology in a sexually dimorphic manner, not overlooking the fact that only few studies have addressed this question directly and yielded significant results. For this purpose, a literature search was performed among the English language articles of the PubMed database using search terms such as sex/gender differences/dimorphism, women/females, polymorphism, pharmacokinetics, pharmacodynamics, pharmacogenetics, pharmacogenomics, cytochrome, depression and antidepressants in various combinations.
Pharmacogenetic analysis of pharmacokinetics-related genetic loci has received considerable attention, mainly due to the marked inter-individual variation in the rate of drug metabolism. Despite being known for many years, this polymorphic response has received increased attention since the pharmaceutical industry is required by the Food and Drug Administration (FDA), as well as other similar authorities, to document the metabolism of a novel drug upon registration. As far as antidepressant treatment is concerned, pharmacogenetics have contributed significantly to the characterization of functional polymorphisms in key drug metabolism genes (extensively reviewed in ). In this context, the cytochrome P450 (CYP) and the multidrug resistance (MDR) gene families have been meticulously studied. Importantly, numerous studies suggest that the pharmacokinetic disposition of widely used antidepressants varies between men and women, with women treated with antidepressants exhibiting a different adverse response profile .
In humans, CYP genes are expressed in the smooth endoplasmic reticulum of hepatocytes, but their expression has also been validated for the kidney, lung tissue, gut mucosa, as well as brain. Of the top 10 drug-metabolizing CYP genes, CYP2D6, CYP3A4, CYP2C19 and CYP1A2 are important for the metabolism of antidepressant drugs . However, research on the CYP2D6 enzyme (debrisoquine/sparteine hydroxylase) has gained ground over the other CYP isomorphs since it catalyzes the metabolism of numerous widely prescribed antidepressants (e.g. fluoxetine, fluvoxamine, paroxetine, imipramine, clomipramine, desipramine). Genetic variations in CYP enzyme loci result in differential metabolism of antidepressant drugs with patient-carriers of specific alleles being characterized as ultra-rapid metabolizers (UM), and thus tending to have lower serum levels of antidepressants at a standard starting dose compared to patients with poorer metabolism (PM) . In contrast, PMs are more likely to experience the toxic reactions at “standard” doses. The CYP450 genotyping test is being implemented in the clinic for the determination of the different metabolizer types, in an increasing number of health institutions [14, 37]. Despite initial scepticism, the elucidation of the metabolizer status of an individual may indeed result in a more rationalized dose escalation of the antidepressant selected by the clinician for the treatment of a given depressive episode.
Sex differences in response to antidepressant treatment have been largely attributed to sex-differentiated pharmacokinetic disposition of psychotropic agents; hormonal fluctuations during the menstrual cycle in women can affect the pharmacokinetics of psychotropic drugs . Interestingly, both the use of oral contraceptives, as well as hormonal replacement therapy may influence the pharmacokinetics of psychotropic agents [32, 33]. Notably, sex differences in human hepatic CYP-catalyzed drug metabolism are well-documented; for instance CYP3A4, the predominant cytochrome P450 catalyst of oxidative metabolism in human liver, is expressed at a higher protein and mRNA levels in women than in men . Even though sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes have recently been detected , to the best of our knowledge, evidence regarding sex-specific influences of CYP genes polymorphisms on antidepressant treatment have yet to be revealed.
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Among the candidate genes that are being evaluated pharmacogenetically, many are selected because of their involvement in pharmacodynamic processes, including transporters, receptors and biosynthetic enzymes that catalyze crucial and rate-limiting steps of monoamine biosynthesis and catabolism. For example, alterations in the central serotonergic system have been implicated both in the pathophysiology of depressive disorders, as well as in the mediation of the therapeutic outcome of antidepressant treatment .
Genetic variants implicated in antidepressant response
Numerous pharmacogenetic studies regarding responsiveness to antidepressants have focused on the genetic variations of the serotonin (5-HT) transporter (SLC6A4; 5-HTT) gene which is located on chromosome 17 in humans . Of particular interest is the functional polymorphism on the promoter of the 5-HTT gene, known as 5-HTT gene-linked polymorphic region (5-HTTLPR) that consists of 16 imperfect 22 base pair repeats. The polymorphic nature of this site involves the presence/absence of two of these repeats. Thus, their absence produces a short allele (S), whereas their presence produces a 44 base pair longer allele (L). It should be noted that even longer alleles have been described in the literature mostly in non-Caucasian populations . The functional implications of this “bi-allelic scheme” are that carriers of the L-allele are characterized by an enhanced expression rate of the 5-HTT, with the opposite being the case for S-allele carriers. Taking into account that the 5-HTT is a direct protein-target for most antidepressant drugs, it has been postulated that L-allele carriers benefit more from the antidepressant treatment. The latter may possibly be attributed to a generalized responsiveness of the serotonergic system owing to the enhanced expression/activity of 5-HTT . Another less studied polymorphism in the 5-HTT gene that has been reported to affect the antidepressive potential is STin2, a 17 base pair Variable Number Tandem Repeat (VNTR) in the second intron of the SLC6A4 locus; this variation has been more consistently reported to have an impact on Asian cohorts [14, 86].
Other genes related to the central monoaminergic neurotransmitter systems have also been the subject of intensive pharmacogenetic screening (Fig. (2)). Among these are the rate-limiting enzyme of 5-HT biosynthesis, tryptophan hydroxylase 1 & 2 (TPH1 & TPH2), inactivation enzymes monoamine oxidases A & B (MAO-A; MAO-B) and catechol-O-methyl-transferase (COMT), as well as 5-HT's targets 5-HT1A and 5-HT2A receptors . In humans, there are two distinct TPH genes located on chromosomes 11 and 12, coding for two different homologous enzymes TPH1 and TPH2. TPH2 is the predominant isoform in the CNS while TPH1 is found in 5-HT-expressing tissues in the periphery and has a major impact only early during brain development . The A218C variant of TPH1 has been consistently reported to affect the antidepressive potential, with the A-allele being associated with slower response rates .
MAO-A is an enzyme located on the X human chromosome, and expressed on the outer mitochondrial membrane catabolizing the deamination of dopamine (DA), norepinephrine (NA), and 5-HT. A VNTR polymorphism located 1.2 kb upstream of the MAO-A coding sequences, consists of 30 base pair repeated sequence present in 2, 3, 3.5, 4, or 5 repeats (R). This polymorphism is functional in that 3.5R or 4R transcribed 2-10 times more efficiently compared to those with 2, 3, or 5R, however its impact on depression/ antidepressant response still remains elusive [13, 14, 58, 88].
COMT on the other hand, is involved in the inactivation of catecholamines (DA, NA). Despite the inconsistent findings, a functional SNP (G472A), that causes a substitution of Valine to Methionine in codon 158 (Val158Met; Met-allele is associated with a three- to four-fold lower enzymatic activity), has also been shown to influence response to antidepressants [14, 71, 72].
5-HT1A receptor mediates inhibitory signals at both pre- and post-synaptic sites, whereas 5-HT2A receptor is primarily located post-synaptically and upon activation sets into motion a molecular cascade that acts in an excitatory manner. Notably, 5-HT1A receptor transcription rate is modulated by a variation (C1019G) in the upstream regulatory region of the gene; the C-allele being associated with the down-regulation of 5-HT1A, which is thought to occur upon medium-term antidepressant treatment, has been associated with a better response to antidepressant treatment [14, 87].
For an extensive and critical presentation of the genetic variants, as well as the candidate systems implicated in the pathophysiology of major depression and antidepressant response, the reader is directed to recent reviews focusing on this matter [13, 14]. Despite the fact that a set of candidate genes has been shown to influence the response to antidepressant treatment, the findings from the different studies have not been consistent . However, recently revealed sex differences in the aforementioned genetic variants have been implicated in both the effectiveness of antidepressant response and in the development of depressive symptomatology.
Sex differences in the genetic variants implicated in depression
At the preclinical level, the serotonergic status of various brain regions implicated in the pathophysiology of major depression has been reported to be affected in a sex-related manner in both chronic and acute animal models of depression [18, 21]. Though sometimes pointing to different directions, most studies agree that both the rates of 5-HT synthesis, as assessed by PET , as well as 5-hydroxy-indoleacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) are sexually dimorphic in humans [40, 41]. In addition, 5-HT1A and 5-HT2A receptor densities have been reported to present sex-related patterns in women versus men, as assessed by radioligand binding studies [42, 43].
Only scant but intriguing genetic evidence reveal sex-specific associations between functional variants of genes implicated in the pathophysiology of major depression and depressive symptomatology per se (Table (1)). 5-HTTLPR is being established as a mediating factor in the impact of early- and ongoing-life stress on mood disorders; the severity of depressive symptoms, anxiety and/or negative affect has been associated with the S-allele in females but with the L-allele in males in a number of studies [44-48], pinpointing the importance of a sex-based genetic approach both in the elucidation of the depressive substrate as well as of the antidepressant response.
Notably, Sjoberg and colleagues (2006) suggested that girls homozygous for the S-allele were more prone to develop depression in view of intra-familial conflict, whereas in boys, the presence of the S-allele conferred protection from depressive outbursts under the same traumatic background . In another context, Brummett and colleagues (2008) studied two populations; one with ongoing stress (caregiving of elderly dementia relatives) and one in which all individuals were raised under low socioeconomic status conditions . Homozygosity for the S-allele was associated with higher risk of depressive symptomatology in women, while the L-allele was reported to play that role for stressed men. In accordance, Gotlib and colleagues (2008) reported that girls homozygous for the S-allele produced higher and more sustained cortisol concentrations in response to a stressful lab test compared to girls with at least one 5-HTLPR L-allele . Furthermore, in a study conducted in adolescents, it was shown that homozygosity for the S-allele of 5-HTTLPR was associated with an increased risk for development of depressive symptoms only in females assigned to high family-based environmental risk . In a sample of 374 women, stressful life events interacted with the 5-HTTLPR variant to predict depressive symptoms; those with the S-allele had significantly higher depression ratings, as compared to those with the L-allele . Moreover, in a predominately female sample, lower expressing 5-HTTLPR alleles were associated with increased severity of major depression in those with moderate to severely stressful life events . It should however be noted that Caspi and colleagues (2003) reported that the S-allele interacts with environmental stress to increase probability of depression later in life, in a sample consisting of both males and females .
In contrast, a recent study reported that the L-allele was associated with melancholic depression, with this effect being restricted to female patients . These results being in accordance with a female-specific association of the L-allele with anxiety-related traits , support the notion that the increased activity and/or density of 5-HTT actually lowers 5-HT availability in the synaptic cleft. This finding may be contradictory to the prevailing observations in the field, however is in line with the “monoamine-deficit” hypothesis of depression .
Low tryptophan levels have been associated with depression and may arise under stressful processes . One meta-analysis has even suggested that tryptophan depletion may cause depression only in women . Interestingly, Porter and colleagues (2008) revealed an association between a polymorphism in the TPH1 gene (A218C), according to which the presence of the C-allele in women was associated with markedly reduced plasma levels of tryptophan .
Further, a study examining a 30 base pair VNTR in the promoter of the MAO-A gene demonstrated that the frequency of the long 4-repeat (4R) allele was significantly increased in depressed women of a Chinese population . These findings were in accordance with a previous study by Schulze and colleagues (2000) who reported that German women with recurrent major depression were characterized by increased frequency of long MAO-A-allele genotypes that have been associated with higher transcription rates of the MAO-A gene . These results suggest that the higher frequency of long MAO-A alleles, that result in elevated MAO-A activity, may contribute to the increased female vulnerability to major depressive disorder . However, these associations were not confirmed in two other studies [92, 93]. Despite the reported limitations, these findings are indicative of a genetic component accounting for the sex-differentiated utilization of monoamines under the influence of the depressive status.
The brain-derived neurotrophic factor (BDNF) gene codes for a neurotrophin that is highly expressed in the CNS, especially in the hippocampus where it plays a role in the proliferation, differentiation and the maintenance of neuronal integrity throughout lifespan . According to the “neurotrophin hypothesis of depression” a reduction of BDNF expression is involved in the pathophysiology of major depression, whereas the use of antidepressants leads to an upregulation of BDNF in the hippocampus of depressed individuals . A functional SNP (G196A) in the BDNF gene that results in the substitution of Val to Met at codon 66 (Val66Met) is a common genetic variation with variable frequency in different populations, which has been associated with anxiety and major depression . Interestingly, a recent meta-analysis by Verhagen and colleagues (2010) revealed that the G196A polymorphism in the BDNF gene is of greater importance for the development of major depression in men than women, with male depressed patients carrying the Met-allele significantly more often than healthy controls .
Sex differences in genetic variants implicated in antidepressant response
Recent pharmacogenetic research on the impact of sex on antidepressant treatment has focused on selective serotonin re-uptake inhibitors (SSRIs), because these drugs represent the first-choice of pharmacological intervention for the treatment of major depression worldwide (Table (2)). Notably, it has been reported that 30-40% of patients do not respond sufficiently to the initial treatment with an SSRI; non-response has been associated with individual differences in pharmacodynamic processes and in this context, partly attributed to the polymorphic nature of certain genes of the serotonergic system (e.g. 5-HTT and 5-HT1A receptor genes) . In addition, SSRIs have been reported to exert sex-differentiated effects on both animal models [60, 61] and humans [62-64]. Therefore, in depth research on whether/which DNA polymorphisms are somehow involved in SSRI responsiveness and if these vary between the two sexes is of great importance for improving the clinical care of these patients.
As far as sex-related influences of DNA variations on the antidepressant response are concerned, a recent study by Smits and colleagues (2008) screened the two most prominent polymorphisms of the 5-HTT gene (5-HTTLPR and STin2) for associations with non-responsiveness to SSRI treatment in a Caucasian population . According to their results, the response of male patients to SSRI treatment was independent of the studied polymorphisms in the 5-HTT locus, whereas in women the 5-HTLPR S-allele was associated with a less favorable response to treatment. These findings were consistent with an earlier study showing that paroxetine efficacy in patients with panic disorder was lower in women with the SS genotype compared to women carrying the L-allele . A recent study lent further support and extended the aforementioned associations; in male and female patients with depression, that were treated for 4 weeks with either SSRIs or non-SSRI drugs, the S-allele was associated with lower antidepressant efficacy in depressed women but not in men, with this result being significant for both types of medication . Moreover, a study by Yu and colleagues (2006) underscored the role of sex in the prediction to the effectiveness of SSRI treatment in a Chinese patient cohort . In this study, the C/C genotype of the C1019G polymorphism of the 5-HT1A gene was considered as a female-specific factor for the prediction of a beneficial outcome with fluoxetine treatment. However, no such association was detected for male depressed patients.
Monoamine metabolism has received considerable attention due to the control it exerts on the availability of monoamines for neurotransmission, while analysis of certain polymorphisms in MAO-A, MAO-B and COMT genes has revealed interesting sex-related associations to the therapeutic outcome of various antidepressants. A 30 base pair VNTR polymorphism in the promoter of MAO-A gene that influences the transcription and MAO-A enzymatic activity, has been associated with the response of depressed women to fluoxetine, in a Chinese patient cohort. In particular, women carrying the shorter 3R-allele (low-transcribers of the MAO-A gene) responded better to 4-week fluoxetine treatment compared to the longer 4R-allele carriers (high-transcribers of the MAO-A gene) . No such association was observed among the male population included in this study. Similar findings were observed in Caucasian patients with depression, who were treated with various antidepressant drugs . Again, the longer MAO-A alleles were associated with a greater risk of slower and less efficient response in female patients only. It should however be noted that other studies have failed to discern any effect of this variant on pharmacoresponse in Major Depression [94, 95, 96]. Another study provided evidence regarding the implication of the functional A644G SNP within intron 13 of the MAO-B gene, in the outcome of treatment with paroxetine only in women with major depression . The aforementioned associations may not be unrelated to the fact that the genes encoding MAO-A and MAO-B are located on the short arm of the X chromosome [58, 73].
Common depressive symptoms can be improved by SSRI treatment, possibly owing to the enhancement of the serotonergic tone that in turn enhances dopamine outflow in the central reward system . Given that the COMT enzyme plays a crucial role in the central degradation of DA, it represents a promising candidate for pharmacogenetics studies. As mentioned, a functional SNP (G472A) in the COMT gene results in a three- to four-fold decrement of the enzymatic activity of the membrane-bound isoform . Notably, a recent study by Tsai and colleagues (2009) conducted in Chinese depressed patients treated with fluoxetine, revealed a sex-dependent association of the COMTVal/Val genotype with poorer antidepressant response, but only in male patients .
Apart from the monoamine-related pharmacogenetic candidates presented, other molecular systems may also be implicated in response to antidepressants. Basic research in animal models implicates the endocannabinoid system both in the pathogenesis of major depression and anxiety, as well as in the mediation of antidepressant response . In a study conducted in a Caucasian cohort of depressed patients receiving various antidepressant medications, the G-allele of a synonymous polymorphism (G1359A) of the cannabinoid receptor CB1 (CNR1) gene was shown to confer a greater risk for resistance to antidepressant treatment, especially in depressed women with high comorbid anxiety . Angiotensin I converting enzyme (ACE) gene is expressed in the CNS and its actions include the degradation of neuropeptides, including substance P . Substance P has been implicated in the pathophysiology of depression, while antagonists for this neuropeptide may alleviate depressive symptomatology [98, 99]. Interestingly, research on an insertion/deletion (I/D) functional polymorphism, represented by the presence/absence of a 287 base pair region within the angiotensin I converting enzyme (ACE) gene has indicated that the D-allele was associated with faster onset of antidepressant therapy (i.e. SSRIs, TCAs etc), but only in female depressed patients .
It has been proposed that the complex interplay between gonadal hormones and monoaminergic genes may account, at least in part, for the sex-dependent responsiveness to antidepressant treatment by modifying gene expression or epigenetic processes [52, 74, 75]. Whether other intrinsic factors are involved remains to be addressed in future, ideally large-scale multiethnic studies.
Overall, there is increasing evidence on how polymorphisms affecting pharmacodynamics influence antidepressant pharmacoresponse and/or the incidence of depression and/or in a sex-dependent manner. However, it is premature to draw definite conclusions on the interplay of sex and genetic polymorphisms in relation to antidepressant response, since very few studies have addressed directly the parameter of sex. In most studies to date, sex was either not controlled for, or at best, was modeled as a covariate. Other major limitations often encountered in such genetic studies typically include a statistically underpowered sample size, different ethnicities, the evaluation of multiple disease phenotypes receiving a mixture of antidepressant treatments, the lack of standardized dosage schemes, as well as others reported in detail in [14, 85].
It is anticipated that “sex-oriented” preclinical research in parallel with clinical pharmacogenetics will expose additional molecular mechanisms pertaining to the pathophysiology of depression and responsiveness to antidepressants that may differentially influence men and women. This could eventually lead to the elucidation of the key-question imposed herein, and specifically as to whether/ which genetic polymorphisms affecting responsiveness to antidepressant treatment are associated with sex and how this knowledge should be used in the clinical setting to select the right drug at the right dose for each patient, ultimately achieving increased response rates in shorter treatment periods.
CONFLICT OF INTEREST
Investigators in the present study acknowledge they do not have an economic interest in, or act as an officer of any extraneous entity whose financial interests would appear to be affected by the present research.
5-HTT gene-linked polymorphic region (5-HTTLPR)
5-hydroxy-indoleacetic acid (5-HIAA)
angiotensin I converting enzyme (ACE)
Brain-derived neurotrophic factor (BDNF)
Cannabinoid receptor CB1 (CNR1)
Cerebrospinal fluid (CSF)
Cytochrome P450 (CYP)
Food and Drug Administration (FDA)
Longer allele (L-allele)
Monoamine oxidases A & B (MAO-A; MAO-B)
Multidrug resistance (MDR)
Poorer metabolism (PM)
Selective 5-HT re-uptake inhibitors (SSRIs)
Serotonin transporter (SLC6A4; 5-HTT)
Short allele (S-allele)
Tricyclic antidepressants (TCAs)
Tryptophan hydroxylase 1 & 2 (TPH1 & TPH2)
Ultra-rapid metabolizers (UM)
Variable nucleotide tandem repeat (VNTR)
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