Needs Assessment: Clinicians need to learn about new psychotherapeutic drugs in late stages of clinical development. This article informs the reader about a new class of antidepressants in development called triple reuptake inhibitors.

Learning Objectives:
• List at least two clinical features of depression thought to be due to deficits in brain dopamine.
• Define what is meant by “triple reuptake inhibitor.”
• Name two triple reuptake inhibitors that have been in Phase II clinical trials.

Target Audience: Primary care physicians and psychiatrists.


CME Accreditation Statement:
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: March 19th, 2008.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by April 1, 2010 to be eligible for credit. Release date: April 1, 2008. Termination date: April 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Liang is research fellow and Dr. Richelson is principal investigator in the Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, and Mayo Clinic in Jacksonville, Florida.

Disclosure: Dr. Liang reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Richelson receives grant support from the National Institutes of Health.

Please direct all correspondence to: Elliott Richelson, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; Tel: 904-953-2439; Fax: 904-953-7117; E-mail: richel@mayo.edu.

  

 

Abstract

A major advance in the pharmacotherapy of depression was the introduction of the selective serotonin reuptake inhibitors nearly 2 decades ago. These drugs succeed in treating depressed patients with few of the side effects common to tricyclic antidepressants, which they largely replaced. However, there are still unmet clinical needs with respect to efficacy, onset, and side-effect profile. The effects of the antidepressants occur almost immediately; however, a therapeutic lag is required to affect meaningful symptom improvement. Not all patients respond to antidepressants well, with some patients undergoing adverse events such as sexual dysfunction. Novel therapies or targets that may reduce side effects need to be addressed. Dopaminergic circuit dysfunction has been linked to depressive syndrome for many decades, and research on serotonin/norepinephrine-containing circuits has largely overshadowed its role in depression. It has been hypothesized that a broad-spectrum antidepressant will produce a more rapid onset and better efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine, in part due to the addition of the dopamine component. Triple reuptake inhibitors (serotonin, norepinephrine, and dopamine reuptake inhibitors) are being developed as a new class of antidepressant. This article presents the involvement of the dopaminergic neurotransmission underlying depressive symptoms, as well as preclinical and clinical trials of developing triple reuptake inhibitors.

 

Introduction

Depression is a prevalent, heterogeneous, and recurrent mental disorder with a lifetime prevalence in approximately 16% of American adults and as much as 21% of the world population. According to the World Health Organization, depression is among the leading causes of disability worldwide. Despite the numerous improvements in antidepressants, there continue to be many unmet clinical needs regarding efficacy, onset of action, and side-effect profile. Although novel targets (eg, corticotrophin-releasing factor receptor) are being researched, current pharmacotherapies for depression are based on the decades-old monoamine (serotonin, norepinephrine, and dopamine) deficiency hypothesis underlying the etiology and pathogenesis of the depressive disorder.1

Pharmacotherapy of depression aims to elevate synaptic levels of the three key monoamines. However, the neglected neurotransmitter in this equation is dopamine, because the most widely used antidepressants that block reuptake of biogenic amines do not block dopamine transporters. There is compelling reason to add dopamine to the mix. To achieve reuptake blockade of all three neurotransmitters—serotonin, norepinephrine, and dopamine—triple reuptake inhibitors have been in development for at least the past decade. After a discussion of the importance of dopaminergic neurotransmission in depression, this article discusses some preclinical research and clinical trials of triple reuptake inhibitors in development.

 

Background

The earliest, modern-day antidepressants were monoamine oxidase inhibitors (MAOIs; eg, phenelzine) and tricyclic antidepressants (TCAs; eg, imipramine). These drugs were found to be effective in treating depression, largely by empirical testing, and were subsequently shown to enhance monoamine levels in brain synapses by preventing their metabolism and transport back into the nerve ending (reuptake). Because of various unnecessary receptor blocking effects, these drugs were not always well tolerated. Therefore, “cleaner” drugs were sought and MAOIs and TCAs were largely replaced by selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, sertraline) and serotonin norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine, duloxetine). These are specifically focused on serotonin and/or norepinephrine transporters with desired effects and fewer interactions with certain neurotransmitters and their receptors, effects that limit the use of MAOIs and TCAs.2-4

Despite higher selectivity and better tolerance by patients, the newer-generation antidepressants are not superior to MAOIs and TCAs in clinical response and remission rates. Their pharmacologic effects occur almost immediately; however, a therapeutic lag occurs before meaningful symptom improvement occurs.5,6 Although the reason for this lag is not completely understood, it is thought to reflect the time required for desensitization of the receptors regulating monoamine release (serotonin [5-HT]1A, 5-HT2C, and α2-adrenergic receptors)7-9 and changes in expression of certain genes (brain-derived neurotrophic factor [BDNF]; neuropeptide VGF).10-12

In addition to the fact that not all depressed patients are satisfactorily treated with these new drugs, there are some unwanted adverse events such as sexual dysfunction, which are hypothetically due in part to the failure of SSRIs or SNRIs to induce similar alterations in dopamine signaling while increasing serotonergic or noradrenergic neurotransmission.13 Despite the dysfunction of dopaminergic circuits, which has been linked to depressive syndrome for decades, research on norepinephrine- and serotonin-containing circuits has largely overshadowed research on the role of dopamine in depression. Dopamine is thought to play a critical role in mediating some depressive symptoms such as anhedonia. Research is being reported on the improvement in depressive symptoms in treatment-resistant patients with addition of a dopamine agonist.14,15 Thus, with this information and the clinical success of SSRIs and SNRIs, there is considerable rationale for targeting all three monoamine reuptake sites (transporters) using drugs that are termed triple reuptake inhibitors (serotonin, norepinephrine, and dopamine transport blockers) in the treatment of depression.16,17

 

Dopaminergic Mechanism in Depression

The mesocorticolimbic dopamine system is involved in motivation, psychomotor speed, concentration, the ability to experience pleasure, and neurogenesis.13,18 There is considerable evidence linking mesocorticolimbic dopaminergic pathways with depression, especially with anhedonia and the lack of motivation observed in many depressed patients.19 Apathy and anhedonia together, defined as a loss of interest or pleasure in normally rewarding activities, are cardinal criteria for a diagnosis of depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.20 Moreover, hippocampal neurogenesis is implicated in the physiopathology of depression and partially underlies antidepressant therapy.21,22

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in depression and especially in major depressive disorder (MDD). This may result from either diminished dopamine release from presynaptic neurons or impaired signal transduction, including changes in receptor number or function and altered intracellular signal processing.13 Impairments of the mesolimbic dopamine system, including reduction in dopamine levels,23 decreased dopamine (D)2/D3 receptor binding,24 and supersensitivity of dopamine postsynaptic receptors25 were seen in animal models of depression and were reversed by ongoing antidepressant treatment.19,24,26 Transgenic mice with a disruption of the prostate apoptosis-response-4/D2 receptor interaction exhibit depression-like behaviors.27 Clinical studies also found lower concentrations of dopamine metabolites, primarily homovanillic acid (HVA), in the cerebrospinal fluid of depressed patients compared to that for healthy individuals, particularly in patients with psychomotor retardation. Dopamine turnover correlated inversely with the severity of depression as measured by the Hamilton Rating Scale for Depression (HAM-D).28 Genetically, more than one vulnerable dopaminergic-related gene may significantly increase the likelihood of developing MDD via the D4 receptor, dopamine transporter, catechol-O-methyl transferase, or the dopamine β-hydroxylase gene.29-31

Drugs that are known to decrease or increase dopaminergic neurotransmission can have depression-like or antidepressant-like effects, respectively. Treatment with reserpine, which depletes synaptic stores of dopamine and other monoamines, and neuroleptics, which block dopamine receptors, down-regulate dopaminergic circuits and can produce depression-like symptoms in humans.32 Conversely, psychostimulants, which increase synaptic levels of dopamine by releasing dopamine or blocking its reuptake, induce a hedonic mood by activation of mesolimbic dopamine transmission. Several drugs acting on the dopamine system have been evaluated for their efficacy in MDD, such as MAOIs and dopamine agonists.13 The efficacy of MAOIs in atypical depression and anergic bipolar depression partly depends on their effect on dopamine metabolism.33 Dopamine agonists bromocriptine and pramipexole exert antidepressant efficacy in a randomized placebo-controlled study in patients with MDD.34,35 In addition, it is suggested that dopaminergic neurotransmission may be a final pathway common for many antidepressant treatments.36 Chronic antidepressants potentiate dopamine transmission by causing supersensitivity of postsynaptic D2-like receptors (ie, D2 and D3), and subsensitivity of D1 receptors occurs preferentially in the limbic system.19 These receptor sensitivity changes may contribute to therapeutic effects of antidepressants.37

Additional evidence that associates dopamine neurotransmission with depression is the high incidence of depression among patients diagnosed with Parkinson’s disease, a neurologic disease involving the degeneration mainly of dopamine-synthesizing neurons. The incidence of depression in Parkinson’s disease is in the range 30% to 50% and prevalence in some surveys is >60%.38 Anecdotally, depression in Parkinson’s disease is very difficult to treat. Overlapping symptoms between depression and Parkinson’s disease such as apathy, anhedonia, sleep-wake dysregulation, and lack of energy correlate with the dysfunction of mesocorticolimbic or nigrostriatal dopaminergic, serotonergic, and noradrenergic circuits in Parkinsonian depression.38

Dopaminergic medication can bring about improvement in episodes of severely depressed mood in Parkinson’s disease patients. Adjunct treatment with dopamine agonists, either pergolide or pramipexole, had significant antidepressant effects in Parkinson’s disease patients according to the Zung self-rating scores or HAM-D.39 Pramipexole showed the greater effect with 61% of Parkinsonian depressed patients reaching the “recovered” points in HAM-D, as compared with only 27% of those on sertraline.40 SSRIs, including fluoxetine, sertraline, citalopram, and paroxetine failed to improve Parkinson’s disease depression,41-43 while beneficial effects of paroxetine, nefazodone, fluoxetine, and venlafaxine were observed in Parkinson’s disease-associated depression in other clinical trials.44-48 Although SSRIs are still the most commonly used drugs to treat depression in Parkinson’s disease, there is a high risk of worsening Parkinson’s disease tremor (possibly due to effects of serotonin-mediated inhibition of dopamine release). Given that the dopaminergic system is involved in the pathogenesis of both depression and Parkinson’s disease, it is hypothesized that triple reuptake inhibitors might have improved efficacy in treating Parkinson’s disease depression with less likelihood of aggravating tremors.

Disturbances in reward functioning in MDD further implicate dopamine neurotransmission in depression. The drug-addicted state shares some underlying neurobiologic substrates and common symptoms with depression and there is a high rate of comorbidity of drug addiction with depression.49 Anhedonia, in addition to being a cardinal criterion for the diagnosis of depression, is also a core symptom required for the diagnosis of drug withdrawal, which is thought to involve a reduction in mesolimbic dopamine neurotransmission. Severity of MDD has been found to correlate directly with the magnitude of the reward experience after psychostimulant (d-amphetamine) treatment.50 Specifically, medication-free, severely depressed subjects experienced greater reward than controls after treatment with a psychostimulant, while mildly depressed patients did not differ from controls. Compensatory mechanisms resulting from the reduction of dopamine release in MDD, such as up-regulation of postsynaptic dopamine receptors and decreased dopamine transporter density, may contribute to the greater effect of amphetamine in these patients. Additionally, the hyperactivity of the hypothalamic-pituitary-adrenal axis in MDD may selectively facilitate dopamine transmission, thus supporting the theory that a depressed patient has increased reward processing of psychostimulants.51

 

Broad-Spectrum Antidepressants: Triple Reuptake Inhibitors

Given the critical role of dopamine circuits in mediating some depressive symptoms, a triple reuptake inhibitor—a broad-spectrum drug combining blockade of dopamine, serotonin, and norepinephrine transporters—is an attractive strategy to treat depression. Hypothetically, this type of drug would produce a more rapid onset and better efficacy (higher response and remission rates) than current antidepressants in part due to the addition of the dopamine component.16 In addition, it is possible that some of the sexual dysfunction related to serotonin transport blockade, seen very commonly with SSRIs,52 would be attenuated or even eliminated due to the addition of the dopamine component. In particular, hyperprolactinemia, which causes impotence in males, would be less likely to occur since dopamine opposes serotonin-promoted prolactin release.53 In addition, due to the link to the dysfunction of dopamine neurotransmission, triple reuptake inhibitors may be of benefit in Parkinson’s disease2 and psychostimulant withdrawal with or without depression.49
Enhancements of BDNF gene expression and hippocampal neurogenesis followed by downstream effects are considered to be important mechanisms after chronic antidepressant treatment.54,55 However, neurogenesis more likely relates to their antianxiety rather than their antidepressant effects.56 A triple reuptake inhibitor antidepressant may show a more robust ability to up-regulate BDNF transcripts than SSRIs,57 assumedly via distinct signaling cascades targeting regulatory segments at different exons.58

A concern with drugs that block dopamine transporters is their potential reinforcing effects and abuse liability.59 Thus, triple reuptake inhibitors will likely receive extra scrutiny by regulatory bodies regarding their abuse liability. This will require preclinical (testing for reinforcing effects in animals) as well as clinical testing. However, just because a drug blocks the dopamine transporter does not mean that it will be abused. Using positron emission tomography (PET), Volkow and colleagues59 showed that dopamine transporter-blocking drugs must induce >50% dopamine transporter blockade and the blockade must be timely (within 15 minutes) to produce reinforcing effects. For example, radafaxine, a hydroxy metabolite of bupropion being developed as a new antidepressant, blocks the dopamine and norepinephrine transporters and is not reinforcing in animals, since animals will not self-administer the drug. In PET studies,43 it shows relatively low potency and slow blockade of the dopamine transporter in human brain.59 These animal and human studies suggest that radafaxine is unlikely to have reinforcing effects in humans. For triple reuptake inhibitors, PET studies of dopamine transporter blockade in humans may be an easy way to test for their tendency for abuse.

 

Developing Triple Reuptake Inhibitors

If these hypotheses are proven correct, the therapeutic profile of triple reuptake inhibitors would offer clear advantages over currently available antidepressants. Although the clinical efficacy of such a broad-spectrum antidepressant has not yet been fully demonstrated, several compounds have entered clinical trials, such as DOV 216,303, DOV 21,947, NS-2359, and SEP-225289. Information on the binding profiles of the known triple reuptake inhibitors is limited. Some data for inhibition at human or rat transporters are listed in the Table (Albany Molecular Research Inc. Drug Discovery Symposium, unpublished data, October 2006).60-63

 

 

 

PRC Series

In collaboration with Paul R. Carlier, PhD (Virginia Tech, Blacksburg, VA), the authors of this article have synthesized a series of compounds based on the structure of venlafaxine (Figure).17 Racemic PRC025 {(1S/1R,2S/2R)-1-cyclohexyl-3-(dimethylamino)-2-(naphthalen-2-yl)propan-1-ol} and racemic PRC050 {(1S/1R,2S/2R)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol} are both highly potent at human serotonin, norepinephrine, and dopamine transporters and also potently inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes.64 Both are active in tests predictive of antidepressant activity in humans including the mouse tail-suspension test and the rat forced swim test.64 PRC200-SS {(1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol} (Figure), which is the more active enantiomer of PRC050, potently binds to the human serotonin, norepinephrine, dopamine transporters (Table) and potently inhibits serotonin, norepinephrine, and dopamine uptake in cells expressing the corresponding transporter.60 Consistent with these in vitro data, in vivo, PRC200-SS (10 mg/kg, ip) significantly increased the extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, HVA, and 5-hydroxyindoleacetic acid compared to levels for saline control (Y Liang, PhD, unpublished data, October 2007). In addition, PRC200-SS dose-dependently decreased immobility in the forced swim test in rats and in the tail-suspension test in mice, with effects comparable to imipramine, but at a much lower dosage.60 The results in these behavioral models do not appear to be from the stimulation of locomotor activity, which would give a false-positive result in these predictive tests of antidepressant activity in humans. Further, PRC200-SS self-administration, which was used as a test of abuse liability, was not observed with rats (Y Liang, PhD, unpublished data, October 2007). To these authors’ knowledge, this is the first study to address the abuse property of a triple reuptake inhibitor. Therefore, it appears that PRC200-SS is a novel triple reuptake inhibitor that possesses antidepressant-like activity. It is expected that PRC200-SS will be in clinical testing in 2009.

 

 

 

DOV Series

DOV Pharmaceutical, Inc. (Somerset, NJ), is developing a DOV series of triple reuptake inhibitors (Table). DOV 216,303 (racemic) is active in the mouse forced swim test, with the reversal of tetrabenazine-induced ptosis and locomotor depression.16 DOV 21,947, as the (+)-enantiomer of DOV 216,303, is effective in the rat forced swim test with an oral minimum effective dose of 5 mg/kg without significant locomotor activity and in the mice tail suspension test in a dose-dependent manner with a minimum effective oral dose of 5 mg/kg.16,61 DOV 102,677 (20 mg/kg, ip) increased extracellular levels of dopamine, serotonin, and norepinephrine in the prefrontal cortex and levels of dopamine and serotonin in the nucleus accumbens, along with reduction of their metabolites in both regions. These results are consistent with the dosage used for antidepressant-like activity in the forced swim test with a minimum effective dose of 20 mg/kg.62 DOV 102,677 was also as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. Further, DOV 102,677 potently blocked volitional consumption of alcohol and reduced the operant response to alcohol.65 DOV 216,303 has already entered into clinical trials. Dose-escalating, placebo-controlled, double-blind Phase Ia trials show rapid absorption following oral administration. Severe side effects in Phase Ia and Phase Ib trials were limited to diarrhea, vomiting, and nausea. Phase I trials indicated DOV 216,303 to be safe and well tolerated at single doses of up to 100 mg and at multiple doses of up to 100 mg/day for 10 days. Phase II trials showed that DOV 216,303 is as effective as the SSRI citalopram in severely depressed patients based on changes in the HAM-D.66

 

NS-2359 (GSK-372475)

NS-2359 (GSK-372475), which was developed by Neurosearch A/S (Ballerup, Denmark) and subsequently out-licensed to GlaxoSmithKline (GSK; United States and United Kingdom), is another triple reuptake inhibitor entering clinical trials. Phase I trials showed it was well tolerated by patients, with increased attention and improved ability to recall verbal information. It is proposed to be a treatment for attention-deficit/hyperactivity disorder. In 2006, GSK initiated Phase II trials in patients with MDD.66

 

Tesofensine (NS-2330)

Tesofensine (NS-2330) is another triple reuptake inhibitor developed by NeuroSearch. It indirectly stimulates cholinergic action, and is suggested by NeuroSearch to be a potential therapy for Alzheimer’s disease and Parkinson’s disease.67 Tesofensine has a longer half-life (8 days) in humans than most other antidepressants. It shows antidepressant-like properties with respect to enhancement of hippocampal neurogenesis and BDNF messenger ribonucleic acid (mRNA) augmentation. Chronic (14 days) but not sub-chronic (5 days) treatment with tesofensine induced increases in BDNF mRNA in the CA3 region of the hippocampus, cytoskeleton protein mRNA in the CA1 of the hippocampus. There was also an increase in hippocampal markers for cell proliferation as measured by immunoreactivity for Ki-67 (a marker of proliferating cells) and NeuroD (a transcription factor regulating neurogenesis).68 Such results correspond with the profiles of current antidepressants.54 In a small Phase IIa pilot study of Alzheimer’s disease, NS 2330 (10.75 mg and 12.25 mg over 28 days) improved aspects of cognition, including attention and ability to store and retrieve information. However, due to inadequate inhibition of dopamine reuptake, tesofensine failed to provide clinical benefit as monotherapy in early Parkinson’s disease compared to placebo in a proof-of-concept, randomized, and double-blind trial.69

 

Others

Sepracor has developed SEP-225289 for treatment of refractory depression and for generalized anxiety disorder. This compound is undergoing Phase I clinical trials. Albany Molecular Research Institute (AMRI; Albany, New York and elsewhere) has developed AMRI CNS-1 and CNS-2 (Table), which have been licensed by Bristol-Myers Squibb (New York, New York; Albany Molecular Research Inc. Drug Discovery Symposium, unpublished data, October 2006). Acenta Discovery Inc. (Tucson, AZ) has designed and synthesized piperidine-based nocaine/modafinil hybrid ligands displaying an improved potency at all three monoamine transporters and particularly for the dopamine transporter and/or norepinephrine transporter.70

 

Conclusion

Clearly, triple reuptake inhibitors hold great promise for the next generation of antidepressants. In the meantime, the available clinical data are too limited to draw any conclusions. Publicly available preclinical data on these compounds are also limited. Some of the in vitro data, presented in the Table, suggest some pharmacodynamic differences among these compounds. Of the compounds listed, PRC200-SS is the most potent at norepinephrine transporter, and AMRI CNS-1 at the serotonin and dopamine transporters.

The rank-order of potency at the various transporters differs among these compounds as well (Table). For example, PRC200-SS is norepinephrine (N)> serotonin (S)>dopamine (D), while DOV 21,947 is S>D>N (Table). It is reasonable to speculate that triple re-uptake inhibitors will have distinctly different clinical profiles depending on their rank order of potency, as well as on their relative potencies at the three transporters. It is also possible to have a perfectly balanced triple reuptake inhibitor, where the potencies at all three transporters are equal. What are the ideal rank order and the ideal relative potency? It is probably easier to answer the latter question, the answer for which derives from occupancy theory. Simply stated, if a drug has a very large range from its most potent to its least potent effect, it may not be possible clinically to achieve a dosage that blocks all three transporters. Thus, a narrow range (10–30-fold) is better. Additionally, it would probably be better to have serotonin transporter blockade as the weakest of the three, to minimize the adverse effects associated with this blockade (eg, sexual dysfunction). Dopamine transporter blockade as the most potent effect may lead to concerns about the abuse potential of the compound. Therefore, the ideal rank order would probably be N>D>S. This would provide a triple re-uptake inhibitor with some nomifensine-like qualities (Table). PP

 

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