Article

Progesterone increase under DHEA-substitution in males

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Abstract

Two case reports of men suffering from excessive fatigue and depression are presented, both treated with 50 or 25 mg DHEA per day over a period of 1 year. Under DHEA treatment one subject reported being less tired and the other experienced improved well-being without depressive episodes and an increase in libido. Investigations of sex hormone parameters in plasma before and under treatment revealed a decrease of testosterone and an increase of progesterone in both, possibly dose-dependent to DHEA application. It is hypothesised that the increase of progesterone is parallel to an increase of its metabolite allopregnanolone (which was not determined), that might explain the improvement in well-being. The increase of progesterone under DHEA supplementation in males should receive further attention.

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... Their samples presented varied characteristics, different ages and both genders. In addition, the dosages used were not consistent among the studies [55][56][57][58] . ...
... In men, testosterone showed a decrease in two studies, yet an increase in most male carriers of Addison's disease, although less expressive than in women 55 . Estradiol was only assessed in one man, and there was an increase 58 . ...
... HIV þ individuals witnessed an improvement in libido; however, this improvement was always associated with a mood enhancement, and was not specifically associated with the effect of DHEA on sexual function 57 . In a case report of two patients, an elderly subject complained of loss of libido whilst a younger patient with depression reported an improvement of depression and libido 58 . ...
Article
Objective: Faced with the growing interest about the action of dehydroepiandrosterone (DHEA) and its benefits, as well as the negative impacts that sexual dysfunctions have on people's quality of life, this systematic review was undertaken with the objective of evaluating the effect of DHEA use on aspects of sexual function. Method: An electronic search was conducted in the databases of PubMed, ISI Web of Science and Virtual Health Library (VHL) combining the terms 'DHEA treatment' and 'DHEA use' with terms such as 'sexual dysfunction', 'sexual frequency' and 'libido'. No limits on time and language were imposed. Clinical studies were considered eligible where individuals for any reason made use of DHEA and if they had any aspect of sexual function assessed. Preclinical studies and systematic reviews were considered ineligible. Results: The search identified 183 references and 38 were considered eligible. DHEA improved aspects such as sexual interest, lubrication, pain, arousal, orgasm and sexual frequency. Its effect was better in populations with sexual dysfunction, especially in perimenopausal and postmenopausal women. Conclusion: Considering the studies currently published, DHEA is effective in improving several aspects of sexual function, but this effect did not reach all the populations studied.
... • Decrease of cortisol levels during DHEA treatment [180] and antiglucocorticoid properties of DHEA [184,185] • Direct modulation of GABA A , NMDA and s-1 receptors by DHEA [181,182] • Metabolization of DHEA to other neuroactive steroids with GABAergic effects [186,187] • Increased testosterone and androgen levels during DHEA treatment, particularly in women with improvement of libido and mood [188] • Neurotrophic effects of DHEA with enhancement of synaptic plasticity [189,166,190] ...
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According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis inhibitor metyrapone and the glucocorticoid receptor antagonist mifepristone in depression has been demonstrated in some small, double-blind, placebo-controlled studies. However, three recently completed Phase III trials failed to significantly separate mifepristone from placebo in depression. Thus, it is unclear at present to what extent new, clinically effective antidepressant therapies can be developed based on the corticoid receptor hypothesis of depression.
... However, the observation of decreased cortisol plasma levels after DHEA administration (Wolkowitz et al., 1999b) and its potential antiglucocorticoid effects in vivo (Browne et al., 1993;Araneo and Daynes, 1995) might play a role for the beneficial effects especially in hypercortisolemic depressed patients. However, also direct modulation of GABA A , NMDA and sigma 1 receptors as well as a metabolism to other steroids (Bloch et al., 1999;Nadjafi-Triebsch et al., 2003;Schmidt et al., 2005) have been suggested to play a role for the antidepressive potential of this neuroactive steroid. ...
Article
Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.
... Administration of DHEA to depressed patients improves their symptoms (Wolkowitz et al, 1997(Wolkowitz et al, , 1999, with daily treatment improving the overall well-being of the patient by preventing depressive episodes, decreasing fatigue, and increasing libido (Nadjafi-Triebsch et al, 2003). Significant improvement also occurs in men and women with midlifeonset major or minor depression upon treatment with DHEA for 6 weeks, according to the Hamilton Depression Rating Scale and the Center for Epidemiologic Studies Depression Scale ratings (Schmidt et al, 2005). ...
Article
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Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate gamma-aminobutyric-acid-type-A (GABA(A)R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (sigma 1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitive-line (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the delta-subunit of GABA(A), but not of sigma 1R mRNA, in FSL rats compared to SD rats. The delta-subunit controls the sensitivity of the GABA(A)R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA(A) agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA(A)), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA(A)Rs in the NAc and VTA.
... The EC 50 for progesterone activation of mPRα, mPRβ and mPRγ in yeast is between 1–3 nM, values that are consistent with the K d 's for progesterone binding to mPRs (~ 5 nM) determined by Thomas et al.[56] These EC 50 values are also close to the physiological concentration of progesterone in human serum, which has been estimated to be between 1–10 nM in men and non-pregnant women in the follicular phase of the menstrual cycle.[57,58] Thus, our data suggests that human mPRα, mPRβ and mPRγ are most responsive to progesterone at physiologically relevant hormone concentrations and would likely function as legitimate progesterone receptors. ...
Article
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Chapter
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The secretion of both growth hormone (GH) and androgens declines with age which may play a role in the senescent changes in body composition and organ function. Among healthy adults abdominal adiposity is an important negative determinant of GH secretion. Surprisingly, abdominal or android obesity seems inversely correlated with testosterone levels in males but not in females. The ability of GH to promote lipolysis and preserve or increase lean body mass has been reappraised in substitution studies in GH-deficient adults. By comparison, adequately controlled studies of androgen replacement in hypogonadal and/or elderly males are few. In view of the physiological and clinical relevance of obtaining information about the aging process, there is a need for controlled experiments addressing similarities and differences between the action of GH and sex steroids in adults.
Article
Progesterone administration induces a reduction of the vigilance state in humans during wakefulness. It has been been suggested that this effect is mediated via neuroactive metabolites that interact with the gamma-aminobutyric, acidA (GABAA) receptor complex. To investigate the effects of progesterone administration on the sleep electroencephalogram (EEG) in humans we made polysomnographic recordings, including sleep stage-specific spectral analysis, and concomitantly measured plasma concentrations of progesterone and its GABA-active metabolites 3 alpha-hydroxy-5 alpha-dihydroprogesterone (allopregnanolone) and 3 alpha-hydroxy-5 beta-dihydroprogesterone (pregnanolone) in nine healthy male subjects in a double-blind placebo-controlled crossover study. Progesterone administration at 9:30 PM induced a significant increase in the amount of non-rapid eye movement (REM) sleep. The EEG spectral power during non-REM sleep showed a significant decrease in the slow wave frequency range (0.4-4.3 Hz), whereas the spectral power in the higher frequency range (> 15 Hz) tended to be elevated. Some of the observed changes in sleep architecture and sleep-EEG power spectra are similar to those induced by agonistic modulators of the GABAA receptor complex and appear to be mediated in part via the conversion of progesterone into its GABA-active metabolites.
Article
To evaluate the anxiolytic 3alpha-5alpha-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls. Thirty-five women with prospectively documented PMS and 36 controls were evaluated. Serum progesterone and allopregnanolone levels were measured on days 19 and 26 of the cycle as determined by urinary LH detection kits. Analysis of variance and Student t tests were used to analyze the data. Allopregnanolone levels were significantly lower on day 26 in the PMS group than in controls (3.6 +/- 0.8 versus 7.5 +/- 1.3 ng/mL; P < .04). Significant differences in the ratio of the metabolite to progesterone also were noted, with a smaller ratio in the PMS subjects (0.9 +/- 0.3 versus 3.2 +/- 1.3 ng/mL; P < .05). There were no significant differences between the PMS and control groups with respect to serum progesterone levels. Subjects with PMS manifested lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase when compared with controls. Diminished concentrations of allopregnanolone in women with PMS may lead to an inability to enhance gamma aminobutyric acid-mediated inhibition during states of altered central nervous system excitability, such as ovulation or physiologic or psychological stress. The lowered metabolite levels could contribute to the genesis of various mood symptoms of the disorder, such as anxiety, tension, and depression.
Article
Prior to three months of age there is little melatonin (MLT) secretion in humans. MLT production then commences, becomes circadian, and reaches its highest nocturnal blood levels between the ages of one to three years. During the remainder of childhood, nocturnal peak levels drop progressively by 80%. In adults, these levels show an additional drop of some 10%, mainly during senescence. The large drop in serum MLT during childhood is probably the result of the increase in size of the human body, despite a constant MLT production after infancy. The additional decline of MLT with higher age may be due to a yet unidentified physiological mechanism accompanying senescence. The biological significance of these MLT alterations remains unknown. Since the discovery of MLT, an immediate sedative action of this hormone has been known. A number of recent studies have demonstrated that MLT indeed exerts a sleep-promoting action by accelerating sleep initiation, improving sleep maintenance, and marginally altering sleep architecture. The potential of MLT in the treatment of insomnia is being explored, and the results are promising. Although in most of these studies pharmacological dosages of MLT have been used, preliminary data suggest that similar effects can also be achieved by physiological hormone concentrations. The latter observation raises the question of whether MLT might be involved in the physiological control of sleep.
Article
Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500 ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males: placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059 microg/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites.
Article
Oestrogens and androgens stimulate collagen matrix synthesis, while progesterone is a competitive inhibitor for the 5 alpha-reduction of testosterone to 5 alpha-dihydrotestosterone (DHT). The anti-androgen finasteride is a specific inhibitor of the 5 alpha-reductase type 2 isoenzyme, associated with anabolic functions. The aim of this investigation is to study the effects of progesterone and finasteride on 5 alpha-reduction of androgen substrates by human gingival fibroblasts. Monolayer cultures of human gingival fibroblasts (HGF) of the 4th 9th passage were established in Eagle's minimum essential medium (MEM). Duplicate incubations were performed with 14C-testosterone/14C-4-androstenedione as substrates and progesterone (P) or finasteride (F), at concentrations of 0.5, 1, 3 and 5 microg/ml, alone and in combination, for 24 h. Similarly, the effects of the alkaline phosphatase inhibitor levamisole (L, 30 microg/ml) and P were studied. Steroid metabolites were analysed and quantified, using a radioisotope scanner. Progesterone inhibited DHT synthesis in HGF from 14C-testosterone by 24-62% (n = 8; p < 0.01). Finasteride caused 59 82% inhibition (n=8;p<0.01). The combination of P+F showed a similar degree of inhibition (68-78%) of DHT synthesis to that of F alone (n = 8; p<0.01). There was 35-56% stimulation of 17beta-HSD (hydroxysteroid dehydrogenase) activity by P, F and P + F (n = 8; p < 0.01). When 14C-4-androstenedione was used as substrate there was 47% inhibition of 5 alpha-reductase activity at higher concentrations of P and 63 and 44% stimulation at 0.5 and 1 microg/ml (n = 8;p < 0.01). F and P + F caused 40-67% inhibition of this activity. P, F and P + F caused 2-2.7-fold stimulation of 17beta-HSD activity in response to all concentrations studied. L inhibited DHT synthesis from both substrates by 36-38%, with further inhibition of 55-70% (n = 4; p < 0.01), with P; this is suggestive of ligand-independent alkaline phosphatase activity mediated by 5 alpha-reductase. Inhibition of 5 alpha-reductase activity by finasteride in gingival fibroblasts is suggestive of target tissue anabolic functions in gingivae and competitive inhibition by progesterone, is suggestive of regulation of hormone mediated tissue responses during repair.
Article
The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months. Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in
Article
The term neurosteroids applies to those steroids that are both synthesized in the nervous system, either de novo from cholesterol or from steroid hormone precursors, and that accumulate in the nervous system to levels that are at least in part independent of steroidogenic gland secretion rates. Glial cells play a major role in neurosteroid formation and metabolism. Several neurosteroids are involved in either auto- or paracrine mechanisms involving both regulation of target gene expression and effects on membrane receptors (including those of neurotransmitters). The neuromodulatory role of neurosteroids in regulating the estrous cycle and pregnancy, stress, memory, and developmental as well as aging processes awaits further investigation.
A multidisciplinary approach for the evaluation and the treatment of androgen deficiency in aging men (ADAM), Organon symposium at the second world congress on the aging male
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Maillhot J. A multidisciplinary approach for the evalua-tion and the treatment of androgen deficiency in aging men (ADAM), Organon symposium at the second world congress on the aging male, Geneva, Switzerland, 2000.
Acute anxiolytic effect of oral administration of progesterone in men: a double-blind crossover study. Presented at the second international symposium on premenstrual, postpartum and menopausal mood disorders
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Anti Aging Sprechstunde Alexander Rö mmler
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DHEA: a comprehensive review In: Proceedings of a workshop by the international health foundation, The Netherlands
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Das männliche Klimakterium oder die besten Jahre des Mannes. Über Wechselwirkungen von hormonellen Veränderungen und physischer Befindlichkeit
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Degenhardt A, Thiele A. Das mä Klimakterium oder die besten Jahre des Mannes. U ¨ ber Wechselwirkun-gen von hormonellen Verä und physischer Befindlichkeit. Forschung Frankfurt 4 Sammelband Med-izin 1997;15:99 Á/109.
Presented at tenth world congress on the menopause
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Hormonprofilveränderungen unter DHEA-substitution bei Patienten mit erektiler Dysfunktion.
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Reiter WJ, Grbovic M, Eisenmenger M, Pycha A. Hormonprofilverä unter DHEA-substitution bei Patienten mit erektiler Dysfunktion. J Urol Urogynä-kol 2001;3:21 Á/5.
Chronic administration of dehydroepiandrosterone (DHEA) does not increase serum testosterone or prostatic specific antigen (PSA) in normal men
  • Vaughn
Neurosteroids:biosynthesis and function
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Hormonprofilveränderungen unter DHEA-substitution bei Patienten mit erektiler Dysfunktion
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Progestagene sind nicht Progesteron, In: Anti Aging Sprechstunde Alexander Römmler; Alfred S Wolf (Hrsg.) Teil 1.Leitfaden für Einsteiger
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