For citation:  Выборных Д.Э., Кикта С.В. Лечение депрессий в гастроэнтерологической практике. Клинические перспективы гастроэнтерологии, гепатологии 2010(6), стр. 21-28 [in Russian]

 

 

Treatment of depression in gastroenterological practice

Vybornykh D.E., Kikta S.V.

The aim of review. To present epidemiologic, clinical and psychopharmacotherapeutic data on depressions at gastroenterological patients. Original positions. According to statistics of the World health organization, 4–5% of the population of globe suffer from depression, thus the risk of development of major depressive episode makes 15–20%. On data of various authors, from 60 to 85% of chronic diseases of alimentary system are accompanied by emotional disorders of different degree. The special place in the structure of depressions at this group of patients is occupied by masked (somatized) depressions with foreground somatic symptoms, while psychopathologic manifestations stay in the background, i.e. the depressive affect is hidden over by various somatic sensations. Antidepressant intake of adequate duration is the basic treatment of depression. The agent, having unique combination of hepatoprotector and antidepressant properties, – ademetionine (Heptral, «Abbott») is one of the drugs, influencing affective sphere. Heptral can be applied by the patient himself as antidepressant at depressions of mild and moderate severity as well as at somatized depressions. It is possible to recommend the following mode of heptral prescription: initial treatment 400 mg/day intravenously or intramuscular for 15–20 days, followed by – maintenance therapy – 2–3 tablets orally per day (800–1200 mg/day). Conclusion. For gastroenterologist it is important to detect symptoms of depression in time in patients for well-timed treatment of developing affective disorders by prescription of antidepressants, in particular – heptral having antidepressive and hepatoprotector properties.

 

Depression (from Latin – suppressed depression, oppression) - psichic disorder, characterized by a a lowered mood with negative, pessimistic, assessment of oneself, one's own provisions in the environment and future. According to statistics of the World health organizations (WHO), 4-5% of the world's population Balls suffer this mental pathology, while the risk of major depressive the episode is 15-20%. By data from WHO and the National the title of psychological health USA, women suffer from this more often than men. At least once in a life is clinically outlined depressive episode of from 7-12% of men and 25% of women. In 60% of cases, recurrent divas, and the risk of their development is higher, the weaker the therapeutic effect in the treatment of previous depressive episode. In 15% observations of patients suffering from depression, perform suicide, which is 60% of all suicide. Medico-social. The significance of depression is determined also because this pathology is the fourth place in the world among other diseases in terms of magnitude costs imposed on which are 97% due to disability of patients and only by 3% - expenses for antidepressants. The problem of depression is also relevant in practice somatic medicine. So, in Sweden, Spain, the USA, Australia, Japan frequency depression in patients with somatic who in turn applied for consultative psychiatric using, reaches 20-29%. By the World Psychiatric Organization, depression observed in 22-33% of hospital- infected patients, 38% of oncological, in 47% of patients with stroke, in 45% - myocardial infarction, in 39% - Parkinsonism [2]. Epidemiological research in the government nonpsychiatric medical institutions (polyclinics, hospitals, city, regional and republican serums, clinical departments research centers dov) testify that the depressed states are observed in average of 23.8% of the examined of patients [1]. However, depression in such health facilities parts are not recognized. In part this is due to the fact that patients include manifestations of mental disorders of various somatic diseases or connect them with the usual reactions on an unfavorable situation in life. According to T.T. Haug et al., from 60 to 85% of chronic diseases of digestive system accompanied by emotional disorders of varying degrees’ expression. In many cases the latter become the first functional diseases. of the gastrointestinal tract and, on the contrary, this frustration can develop as a reaction on the diagnosis, violations of the usual lifestyle caused by the disease and the need for semi-treatment. Both in that, and in another case without correction of emotional-it is very difficult to achieve positive results. With a high level of diagnostics of gastrointestinal tract pathology, it’s not always possible for the to reveal depression and do not know, how to lead such patients. Together with the depression is a factor, aggravating the course of the main (gastroenterological) because it prevents establishing a constructive contact between the patient and the physician oppresses the will and initiative-the patient, reduces adherence to (compliance). But the most significant aspect of the volume is suicidal risk: 2/3 of patients with diagnosed severe depression are to suicide, 10-15% of which influence it [13].

Diagnostics

In the modern International classification of diseases - ICD-10, in which mental and Behavioral Disorders are classified by syndrome- principle, the main tion is given to the picture of the observed disorders of the following standardized diagnostic criteria [4]. Diagnostic criteria- depression (depressive

episode) The main symptoms are:

  • decreased mood, prominent in comparison with the inherent patient, the prevailing almost daily and most days and continuing not less than 2 weeks regardless of the situation;

  •   a clear decline in interest or pleasure from usually associated with the lively emotions;

  • energy reduction and fatigue.

  Additional symptoms:

  • • decreased ability to concentration and concentration attention;

  • • a feeling of insecurity in yourself;

  • • ideas of self-abasement and / or guilt (even with lungs

  • depressions);

  • • gloomy and pessimistic vision of the future;

  • • thoughts or actions related to with suicide;

  • • disturbed sleep;

  • • decreased appetite.

For additional diagnosis, of depression apply so called the scale of depression. There are a lot of such scales and they psychiatric or psychologists for assessment and verification depressive states. There are several types classification of depression in the form the authors' approaches: on the principle of endogenous – adjustment disorders in terms of etiology, in form, etc.

The most typical is the principle, when a kind of classification space, on which the constitutional, somatogenic, psychoreactive and endogenous factors. In accordance with the etiological vectors are three large types of depressions - reactive- and neurotic (where psychogen- constitutional and constitutional are considered the main reasons), endogenous, as well as symptomatic organic and organic. Traditionally, the structure depressive disorders simple (melancholic) anxious, adynamic, apathetic and dysphoric and complex (senestoiphondritis- with delusions, hallucinations and catatonic disorders) depressive syndromes. In addition, the so-called atypical depression, which are most often found in an outpatient or general zinc practice. To them carry- primarily masked (somatized) depression.

Under such forms it is customary to understand depression, in clinical whose picture on the first plan are somatic symptoms, and psychopathological manifestations remain in the shadows, that is, depressive affect for a variety of body sensations. Although all research the states as a depression, giving they have different names (masked, hidden, latent, foggy, worn out, vegetative, somatized depression, depressive equivalent, depression without depression and so on), such an abundance of terms testifies to the complexity of the atypical problem depressions related to the issue- etiopathogenesis, clinical differentiation, nosological accessories, therapies, etc.

Masked depression can manifest in the following forms:

  • psychopathological disorders - anxious-phobic, obsessive-compulsive (obsessive), hypochondriacal, neurasthenic;

  • violations of biological rhythm - insomnia, hypersomnia;

  • vegetative, somatized and endocrine disorders - vegeto-vascular dystonia syndrome, dizziness, functional disorders of internal organs, neurodermatitis, itchy skin, anorexia, bulimia, impotence, menstrual irregularities;

  • in the form of algia - cephalgia, cardialgia, abdominalgia, fibromyalgia, neuralgia (trigeminal, facial nerve, intercostal neuralgia, lumbosacral radiculitis), spondyloalgia, pseudo-rheumatic arthalgias;

  • pathocharacter disorders - impotence disorders (dipsomania, drug addiction, substance abuse), antisocial behavior (impulsivity, conflictness, outbreaks of aggression), hysterical reactions (touchiness, tearfulness, tendency to dramatize the situation, desire to draw attention to one's ailments, accepting the role of the patient).

Most often, gastroenterologists have to deal with a masked (somatoform, somatization) depression, when the depressive nucleus proper is masked by complaints and symptoms from the gastrointestinal tract and other internal organs. Such patients are treated for a long time and sometimes without results by general practitioners, since it is quite difficult to recognize such depression. The most frequent gastroenterological manifestations of depression - nausea, vomiting, dry mouth, belching, flatulence, constipation, diarrhea, abdominal pain, irritable bowel syndrome (IBS) are also not specific. It should be remembered that depression can cause gastrointestinal diseases or be secondary to gastroenterological pathology and its treatment.

Signs of depression are most likely to be detected in patients suffering from functional gastrointestinal diseases, such as functional dyspepsia,  abdominal pain, which has no organic cause, IBS. Depression can also be detected against a background of chronic diffuse liver diseases of various genesis and their complications: viral hepatitis, alcoholic liver disease, non-alcoholic cirrhosis, hepatic encephalopathy, as well as in persons receiving interferon therapy and undergoing liver transplantation.

Depression is supposed to have its endogenous basis in the form of certain mechanisms of neuromediation and can be included in the personality reaction to a somatic disease, largely determining the success or failure of therapeutic and rehabilitation measures. According to the generally accepted concept, depression is primarily a shortage of serotonin mediation, a lack of serotonin in synaptic transmission. In the synaptic gap, the molecules of serotonin come from the vesicles of the presynaptic neuron. The liberated molecules bind to the corresponding receptors of the postsynaptic neuron, and if there is a sufficient number of them, then this connection and the transfer of momentum provide active activity, good mood, working capacity.

Part of the molecules of serotonin from the synaptic cleft through the molecular pump goes back to the presynaptic neuron and here it is destroyed by the enzyme monoamine oxidase contained in the mitochondria. Part of the serotonin, which failed to disintegrate with this enzyme, is again included in the serotonin vesicles of the presynaptic neuron and commits a new cycle of such a circuit.

The origin of somatized depressions remains unclear, but at least three mechanisms can be considered as a hypothesis:

  • latent depression reveals subclinical somatic and neurological pathology, i.e., causes its decompensation, manifesto;

  • hidden depression is combined with real somatic syndromes (bronchial asthma, neurodermatitis, joint diseases, allergic phenomena), pathogenetically related to the depressive state. Effective treatment of depression can result in the complete elimination of psychosomatic syndromes and compensation for overt and subclinical somatic pathology;

  • latent depression imitates somatic disorders due to the inherent nature of the internal picture of the disease.

   With the purpose of timely diagnosis of hidden depressive states, a set of symptoms can be proposed that seems quite reliable:

  •  the onset of the disease is often not associated with the effects of psychogenic, somatogenic and exogenous-organic factors;

  • a phase course - in the anamnesis it is possible to meet indications on the frequency of periods of malaise, weakness, nervousness, decreased mood, expressed sleep disorders and other disorders characteristic of this variant of depression. The duration of the phases is months and years. There may be episodes of mild hypomania;

  • hereditary aggravation in the line of affective psychoses. The symptomatology of a proband (relative) disease can have a significant similarity to the morbid disorders observed in the immediate family;

  • daily fluctuations in mood and well-being (deterioration in the morning, in the morning, with spontaneous improvement in the afternoon, at night - "evening intervals");

  • a vital shade of a low mood ("heaviness on the heart, heart aches, cramps, squeezes") with persistent sleep disorders, anorexia, decreased libido, a sense of decline in strength. Irritability is observed in children and adolescents;

  • a noticeable decrease or addition of body weight without using a diet (more than 5% per month), a prolonged loss of appetite;

  • a noticeable loss of interest in almost all activities (work, hobbies, household chores), which continues, as a rule, day after day for almost the whole day (the so-called anhedonia);

  • the presence in the mental state of indications of the phenomena of ideator and psychomotor inhibition, reproductive memory disorders, symptoms of painful mental anesthesia, depersonalization, derealization;

  • Obsessive thoughts about death (not only fear of death), repeated thoughts about suicide with or without plan, or attempted suicide;

  • genereal somatic and vegetative disorders with latent depression, do not fit into the clinical picture of any specific somatic disease. Nevertheless, there are forms of latent depression that show a significant similarity with manifestations of somatic diseases. The term "masked" is adequate for these forms.

Five of these symptoms should be noted for at least 2 weeks and at the same time there should be a clear deterioration in personal functioning: a reduced mood, loss of interest or pleasure, and so on.

Treatment

Adequate in duration antidepressant medication is the basis of depression treatment. The main indications for the appointment of antidepressants in gastroenterology are functional disorders of the digestive tract, chronic diffuse liver diseases, persistent pain syndrome in chronic pancreatitis, obesity, eating disorders. It is important to know under what diseases and what drugs to use in their work.

Tricyclic antidepressants (TCAs) are part of the treatment algorithm for IBS. Their effectiveness has been demonstrated in several randomized controlled trials and meta-analyzes [18]. The effect on overall gastrointestinal symptoms compared with placebo was significant: the risk ratio was 4.2, 95% confidence interval 2.3-7.9. Reliably, the results of the standardized pain assessment scale also improved. The benefits of using TCAs in patients with chronic pain syndrome include an independent improvement in mood and anxiety reduction. The mechanism of therapeutic action of these drugs in IBS is unclear, but it probably is not limited to the anti-depressive effect, since antidepressants are effective in IBS at doses much lower than the therapeutic ones for depression. It is suggested that antidepressants change the physiology of the intestine, affecting the intramural nerve plexuses.

Currently, TCAs are used primarily in low doses (10-50 mg / day) and are recommended for the treatment of pain and sleep disorders associated with IBS with prevalence of diarrhea. Their initial dose is usually 10 mg per night, especially in the elderly. Every 7 days it should be increased by 10 mg to 50 mg. If a significant effect on the symptoms of IBS is not observed, and the side effects are not expressed, the dose of the drug can be increased even more.

However, TCAs have a number of shortcomings that significantly limit their use. Blockade of muscarinic receptors causes sedation, dry mouth, visual impairment, constipation, urinary retention, memory dysfunction. Blockade of alpha-1-adrenergic receptors can lead to orthostatic hypotension, reflex tachycardia. This is more common in elderly people and patients taking other drugs with similar effects. The blockade of H1-histamine receptors can contribute to weight gain. TCAs slow cardiac conduction and have antiarrhythmic action. Accordingly, their use should be avoided in patients with impaired cardiac conduction, with reduced ventricular function, in patients with prostate adenoma, neurogenic bladder, acute angular glaucoma, dementia. In addition, TCA quite often enter into unwanted interactions with drugs of thyroid and steroid hormones, digoxin, antiarrhythmics (verapamil), alpha-adrenoblockers (propranolol), anticoagulants (warfarin).

Recently, selective serotonin reuptake inhibitors (SSRIs) have been increasingly used as an alternative to TCAs. With a comparable antidepressant effect, their safety is an order of magnitude higher. Although only a single SSRI was performed in the functional pathology of the digestive tract, the data obtained on their efficacy in chronic pain indicate the possibility of using these drugs in IBS. Some studies have shown that SSRIs accelerate intestinal transit, so it is believed that they are more effective in IBS with a predominance of constipation.

Nevertheless, the side effects of SSRIs should not be underestimated. Most often there are violations of the digestive tract: loss of appetite, nausea, less often vomiting, diarrhea, constipation. Another serious side effect: violation of sexual function. SSRIs are active inhibitors of the cytochrome P450 system responsible for the metabolism of most drugs, so patients with liver diseases should be used with caution. The most unfavorable are the combinations of SSRIs with cardiac glycosides (digoxin), beta-adrenoblockers (propranolol), indirect anticoagulants (warfarin), prokinetics (cisapride), antihistamines (terfenadine, astemizole).

It should be noted that antidepressants in gastroenterological practice can be used in both full and reduced doses. For the treatment of concomitant psychopathology (depression, anxiety disorders, etc.), full therapeutic doses of TCAs or SSRIs are used. Low doses allow to influence visceral sensitivity, motility and secretion of the gastrointestinal tract, as well as suppress the central perception of the pain coming in the form of afferent signals from the digestive tract. Do not forget that antidepressants themselves can have a hepatotoxic effect. According to the severity of this effect, drugs can be divided into three groups: with a low risk of hepatotoxic effects (paroxetine, citalopram, mianserin, tianeptine - these drugs can be prescribed to patients with concomitant severe liver pathology in usual doses); with moderate risk (amitriptyline, trazodone, fluoxetine, moclobemide - they can be prescribed to patients with severe liver disease in reduced daily doses); with a high risk of hepato-toxic effects (sertraline-is contraindicated for hepatic insufficiency).

A special place among the drugs affecting the affective sphere is the drug, which has a unique combination of properties of the hepatoprotector and antidepressant-ademetionine (Heptral®, Abbott). Ademethionine (B-adenosyl-1_-methionine) is an active sulfur-containing methionine metabolite, a natural antioxidant and an antidepressant, formed in the liver in an amount of up to 8 g / day and present in all tissues and body fluids, in the highest concentration - in places of education and consumption, t e. in the liver and brain. Decrease in biosynthesis of hepatic ademetionin is characteristic for all forms of chronic liver damage. In numerous experimental and clinical studies, the effectiveness of ademetionine as a hepatoprotector has been proved, as doctors are well aware of and therefore use it precisely in this capacity [8]. Unfortunately, clinicians are not always sufficiently aware that the drug has a pronounced antidepressant activity; moreover, it is considered as an atypical antidepressant-stimulant.

Antidepressant activity of ademetionine is known for more than 20 years, but a general concept that would explain the mechanism of antidepressant action of this compound has not yet been developed. Obviously, it differs from the mechanism of action of antidepressants of all chemical groups known to date. Ademethionine is usually attributed to atypical antidepressants, and its neuropharmacological properties are associated with stimulating the formation of neurotransmitters [16].

The first observations confirming the effectiveness of ademetionine in depression were published in the 1970s. Clinical studies have been performed in Germany, Italy, the United Kingdom and the United States of America. The results confirmed that with intravenous or intramuscular injection the drug is significantly more effective than placebo. Some studies have found that oral ademetionine at a daily dose of 1600 mg is effective in patients with depression.

Currently, ademetionine is used in psychiatric practice precisely as an antidepressant for the treatment of depression, alcoholism, drug addiction and affective disorders. A meta-analysis of the results of 19 comparative clinical trials involving 498 patients with depressions of varying severity confirmed the statistically significant superiority of ademethionin (heptral) therapy compared with placebo (by 38-60%) and TCA-comparable efficacy with incomparably better tolerability and safety. Ademetionine statistically significantly exceeded the efficacy of placebo and TCA in recurrent endogenous and neurotic depressions resistant to amitriptyline, differing from the latter in the ability to interrupt relapses and the absence of side effects.

Almost all researchers note a more rapid development and stabilization of antidepressant action of ademetionine (1 and 2 weeks, respectively) compared with traditional antidepressants, especially with parenteral use. In an open multicenter clinical study in 195 patients with depression, remission occurred after 7-15 days of parenteral administration of the drug at a dose of 400 mg / day. The most distinctly positive effect of therapy is manifested with somatization of depression. Clinical signs of improvement are noted from the second week of treatment, which is expressed by reduction of somatization disorders and proper hypothyroidism. Subjectively, the action of ademetionin is characterized by normalization of muscle tone, increased activity, improved exercise tolerance, restoration of the ability to experience pleasure. The drug can be used in the treatment of non-psychotic depression, in particular asthenic. Therefore, ademetionine (heptral), especially taking into account its somatotropic action, is one of the tools preferred for use in general medical practice [12].

B.L. Kagan et al. also describe ademetionin as a safe and effective antidepressant with a minimum of side effects and a rapid onset of the effect. The authors nevertheless indicate that the drug can induce mania in those patients in whom its symptoms have not been previously noted [14].

There is a report that, with the intensification of antidepressant therapy (conducted by SSRIs), the introduction of ademetionine into the therapeutic regimen is accompanied by the overcoming of resistant depression [6].

In the G.M. Bressa demonstrated a higher efficacy of heptral in the treatment of depressive disorders compared with placebo and traditional tricyclics [9].

A.B. Smulevich et al. showed the efficacy of heptral in dysthymic disorders, especially somatized dysthymia. The authors note that the effect of traditional antidepressants (TCAs) in somatisated dysthymia directed to depressive affect does not lead to a "rupture" of the mechanism of the pathological friendly association of comorbid disorders and, accordingly, is not sufficiently effective. In order to provide a clinical effect of psychopharmacotherapy in such cases, the drug must have a combination of properties that affect the depressive affect, on the one hand, and somatopsychic disorders, on the other. It is precisely this action that has the preparation of heptral [5]. R. Delle Chiaie et al. reported the results of two multicenter studies performed to compare the efficacy of the two drugs. It was shown that the effect of oral administration of ademetionine in a daily dose of 1600 mg or 400 mg intramuscularly is comparable to the effect of oral imipramine at a daily dose of 150 mg, but the first is significantly better tolerated [10].

D. Mischoulon and M. Fava performed a literature review on the problem of the effectiveness of ademetionine and concluded that the oral and parenteral forms of the drug are effective in large depression. In many studies, it has been shown that the antidepressant effect occurs much earlier than with the use of traditional antidepressants, which is confirmed by the studies of other authors [11]. The drug can be given both in the form of monotherapy, and as an additional means to enhance the effect of traditional antidepressants.

Ademetionine is well tolerated and has a small amount of side effects, so it can be recommended to patients with a poor response to traditional antidepressants. While using it, no toxic side effects were found, but the probability of manifestation of anxiety, as well as violations of the manic spectrum in patients with bipolar disorder, was noted. The drug is recommended in daily doses of 400-1600 mg, but in some cases to achieve antidepressant action requires a daily dosage above 3000 mg.

The authors believe that the most suitable for ademetionin treatment are patients with moderate depressive symptoms in whom traditional antidepressants do not give the desired results or are poorly tolerated. The use of ade-methionine as a supplement to traditional drugs can sometimes achieve the most complete antidepressant effect, but caution is necessary, since not all interactions of ademethionine with other drugs have been studied [15].

T.V. Reshetova et al. note that from the whole spectrum of psychotropic action in heptral the ability of influence on asthenodepressive syndrome is most pronounced. Heptral has a reliable antidepressant effect, although it is significantly less pronounced than that of coaxil and cipramil. This makes it possible to determine its place in the treatment of depression after the main multimonthly use of antidepressants to maintain the effect and hepatoprotective effect (since the vast majority of antidepressants have a negative side effect on the liver). In addition to psychotropic and hepatotropic effects during treatment with heptral, a reduction of many associated pathological conditions, mainly immunodeficiency, is observed. This suggests that the research is promising in the direction of the general toning and immunomodulating action of the drug [3].

With regard to the appointment of heptral with a specific severe concomitant pathology, R.A. Shippy et al. studied its effectiveness in HIV-infected patients and came to the conclusion that it is a safe and effective drug in this category of patients [17].

Traditionally, heptral as an antidepressant is administered orally, intramuscularly and intravenously. With intensive therapy (for the first time 2-3 weeks of treatment) 400-800 mg / day is administered intravenously (very slowly) or intramuscularly for 15-20 days; the powder is dissolved only in a special attached solvent (L-lysine solution) immediately before use. For maintenance therapy, use inside 800-1600 mg / day between meals (swallow without chewing, preferably in the morning, given the stimulating nature of the drug). The duration of therapy depends on the severity and course of the disease and is determined by the physician individually.

For elderly patients, treatment should be started at the lowest recommended dose, taking into account a decrease in hepatic, renal or cardiac function, the presence of concomitant pathological conditions, and the use of other drugs.

Thus, depressive states - both explicit and masked - are widespread in gastroenterology, where their frequent combination with functional gastrointestinal pathology and chronic diffuse liver diseases makes it difficult to treat and reduces the quality of life of patients. Rational use of antidepressants not only allows to reduce the severity of depressive disorders, but also has a positive effect on gastrointestinal function (visceral sensitivity, motor and secretion). In contrast to classical antidepressants and other psychotropic drugs, ademetionine (heptral) does not possess hepatotoxicity - on the contrary, it has a combined hepatoprotective and antidepressant effect. Thanks to a unique combination of effects and high safety, it seems to be considered as a universal drug of choice for widespread use in gastroenterology, hepatology and psychiatry.

Conclusions

1. For a gastroenterologist, it is important to identify in good time the signs of a depressed state in the patients being monitored for their timely relief by prescribing antidepressants. The main signs of depression are: a decrease in mood, evident in comparison with the patient's usual norm, prevailing almost daily and most of the day and lasting at least 2 weeks, regardless of the situation; a clear reduction in interests or pleasure from activities usually associated with positive emotions; reduced energy and increased fatigue.

2. Heptral (ademetionine) has a double action - a gastroprotector and a stimulating antidepressant.

3. The drug can be used alone as an antidepressant for depression of small and medium severity, as well as somatization of depression. Heptral, which has a minimal amount of side effects, occupies a special place in the treatment of depressive conditions observed in gastroenterological practice, where their high prevalence is noted, in particular, in patients with liver pathology.

4. With the reception of heptral, the antidepressant and anti-anxiety effect quickly sets in (improvement is observed after 3-7-14 days depending on the severity of the condition).

5. With an improvement in the mental state, patients become more prone to compliance - therapeutic cooperation with a doctor and willingly follow medical appointments.

6. In the treatment of depression in patients with gastroenterological profile, the following scheme of heptral administration can be recommended: initial therapy 400 mg / day intravenously or intramuscularly for 15-20 days, further maintenance therapy - inside 2-3 tablets / day (800-1200 mg / day).

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