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Director's Report to the National Advisory Council on Drug Abuse - May, 2004



Research Findings - Basic Research

Design of Novel Peptide Ligands that have Opioid Agonist Activity and CCK Antagonist Activity for the Treatment of Pain

There is a need for a new paradigm in drug discovery for pathological conditions including disease states such as neuropathic pain and conditions of opioid analgesic tolerance. It is now known from multiple experimental approaches that many disease states lead to changes in expressed proteins (adaptation/neuroplasticity). Drug design based on normal states is inadequate or even possibly counter-indicated. Therefore the system changes that have occurred must be considered in any treatment for the disease. Such "systems changes" are clearly evident in neuropathic pain and in conditions of opioid tolerance where opioids can actually heighten pain. In these pain states there are increased levels and/or activity of pronociceptive neurotransmitters such as cholecystokinin (CCK) and their receptors. CCK and enkephalins and their receptors are co-localized in the CNS and, as a pronociceptive peptide, CCK acts as an "antiopioid" and alternate analgesic to diminish opioid antinociception. In view of these and other findings, NIDA grantee, Dr. Victor Hruby and colleagues have investigated a new paradigm for drug discovery aimed at treatment of pathological pain (such as neuropathic pain) and in conditions of opioid tolerance. In this approach a single peptide or peptidomimetic molecule that can interact with opioid receptors as agonists and at CCK receptors as antagonists is designed. Specifically, compounds that are agonists at opioid mu or delta receptors and antagonists at CCK-1 or CCK-2 receptors (preferably both representing a "balanced" CCK receptor antagonist) are developed. It is postulated that such a molecule would show superior efficacy to opioid agonists for the treatment of pathological pain states since it would block the antiopioid effects of CCK and be resistant to the development of paradoxical opioid-induced pain and antinociceptive tolerance. In this paper, Dr. Hruby and his colleagues report progress toward these objectives using various approaches to rational peptide ligand based drug design. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH2 (i.e., RSA 601), which have the designed properties. Hruby, V.J., Agnes, R.S., Davis, P., Ma, S-W., Lee, Y.S., Vanderah, T.W., Lai, J. and Porreca, F. Design of Novel Peptide Ligands which have Opioid Agonist Activity and CCK Antagonist Activity for the Treatment of Pain. Life Sciences 73, pp. 699-704, 2003.

The Effect of Hair Color on the Incorporation of Codeine into Human Hair

The purpose of this study was to determine if codeine, as a model compound for abused drugs, would be incorporated into black, brown, blond, or red hair as a function of melanin concentration. Male and female Caucasians with black (n=6), brown (n=12), blond (n=8) or red hair (n=6) and non Caucasians with black hair (n=12), aged 21-40 years of age were administered oral codeine phosphate syrup in a dose of 30 mg three times a day for five days. Twenty-four hours after the end of the treatment period, a 30 mg codeine dose was administered and the subject's plasma area under the concentration time curve (AUC) for codeine was determined. Codeine and melanin were measured in the first 3 cm of hair closest to scalp prior to and 1,4,5, 6,and 7 weeks after dosing. The quantitative and qualitative melanin profiles were determined for each subject's hair to provide an objective measure of hair color. The plasma concentrations of codeine were measured to eliminate differences in the bioavailability and clearance of codeine as factors that might account for the differences in codeine hair concentrations. The mean hair codeine concentrations 5 weeks after dosing were 1,429 pg/mg in black hair; 208 pg/mg in brown hair; 99 pg/mg in blond hair; and 69 pg/mg in red hair. In black hair, codeine concentrations were 2,564 pg/mg for Asians and 865 pg/mg for Caucasians. Similar concentration relationships were observed at weeks 4, 6, and 7. A strong relationship between the hair concentrations of codeine and melanin was observed. These data demonstrate that the interpretation and reporting of hair test results for codeine are influenced by hair color. After this dosing protocol, the proposed federal guideline cut-off of 200 pg/mg of codeine would result in 100% of subjects with black hair and 50% of subjects with brown hair being reported as positive, and subjects with blond or red hair would be reported as negative. The incorporation of these drugs into hair should be studied carefully in humans to ensure the appropriate interpretation of drug concentrations. Rollins, D.E., Wilkins, D.G., Kruger, G.G., Augsburger, M.P., Mizuno, A., O'Neal, C., Borges, C.R. and Slawson, M.S. Journal of Analytical Toxicology, 27, pp. 545-551, 2003.

Morphine Tolerance and Development

In a recent paper, Dr. Gordon Barr and Dr. Hongbo Zhu report their findings on ontogeny of N-methyl-D-aspartate (NMDA) receptor mediated morphine tolerance in the postnatal rat. This study is the first to provide conclusive evidence that NMDA receptor antagonists are not effective in attenuating tolerance in the newborn rat and that there is a transition age, around the second postnatal week in the rat, for NMDA receptor antagonists to be effective in suppressing opiate tolerance and withdrawal. This study was undertaken because of the known effectiveness of NMDA receptor antagonists to inhibit the development of morphine tolerance in adults and the dramatic changes that occur in NMDA receptors during the first few weeks of postnatal life. Zhu, H. and Barr, G.A. Ontogeny of NMDA Receptor-Mediated morphine Tolerance in the Postnatal Rat. Pain. 104, pp. 437-447, 2003.

Mixed Mu Agonists/Delta Antagonists

There is a continuing effort and interest in developing ligands exhibiting agonist action at the mu receptor for purposes of chronic pain treatment, but which also possess antagonist properties at the delta receptor, in order to lessen or minimize the known side effects of mu ligands, such as respiratory depression and development of tolerance/dependence. Evidence has been provided by immunoprecipitation and immunoblotting results of an interaction or complex formation between mu and delta receptors, when they are co- expressed in COS cells. These co-expressed receptors showed altered binding profiles (reduced affinity of morphine, DAMGO, and DPDPE) as compared to the values reported in separate cell expressions of mu or delta receptors. Additionally, the development of acute tolerance and dependence in mice administered morphine could be inhibited by pretreatment with the delta antagonist naltrindole (NTI). More recently, it has been reported that the pseudopeptide TIPP[psi], a delta antagonist (lacking mu or kappa receptor antagonism), is quite effective in suppressing tolerance and dependence in rats during chronic morphine treatment. Previous efforts by Dr. Subramaniam Ananthan and associates have suggested that the binding properties of pyridomorphinans may be modified by the particular choice of 5' (meta) substituent on the pyridine ring, resulting, in one case, with a p-chlorophenylpyridine derivative of naltrexone, having in-vivo antinociceptive activity in mice, without the development of tolerance upon repeated injections. The compound also produced fewer signs of withdrawal than with naloxone, in a morphine-dependent rodent model. However, this compound, when tested in a GTPgammaS functional assay, showed very little stimulation activity as an agonist either in guinea pig membranes, or in cells expressing the mu or delta receptor. The authors have now reported the preparation and pharmacological evaluation of additional pyridomorphinans made from naloxone, oxymorphone, and hydromorphone, some of which show "mixed" mu agonism and delta antagonism. In terms of structure-activity relationships, an unsubstituted pyridine ring led to comparable affinity for the mu and delta receptors, while the introduction of an aryl substituent, particularly 4-chlorophenyl or 2,4-dichlorophenyl at the 5' position of the pyridine ring increased the delta antagonism, while retaining sufficient mu agonist potency. These latter two compounds showed nanomolar antagonist constants in the mouse vas deferens assay (displacement of the delta agonist DPDPE) and nanomolar inhibition constants in the functional GTPgammaS activity at the delta receptor, as well as nanomolar agonist IC50 constants in the guinea pig ileum assay (inhibition of the mu agonist PL-017). They both exhibited analgesic activity in the mouse tail-flick assay, and one of them retained its analgesic activity upon repeated icv injection. The design of these ligands, in which the binding at the delta receptor has been increased relative to that at the mu receptor, has resulted in several promising examples of combined in-vivo delta antagonism and partial to full mu agonism. Ananthan, S., Khare, N.K., Saini, S.K., Seitz, L E., Bartlett, J.L., Davis, P., Dersch, C.M., Porreca, F., Rothman, R.B., and Bilsky, E.J. Journal Medicinal Chemistry, 47, pp. 1400-1412, 2004.

Gestational Nicotine Exposure Attenuates Nicotine-Stimulated Dopamine Release in the Nucleus Accumbens Shell of Adolescent Lewis Rats

The effects of chronic gestational exposure to nicotine on the nucleus accumbens dopamine response to acute nicotine were determined during adolescence (postnatal day 29-36) in cross-fostered and noncross-fostered Lewis rats. In both males and females, gestational nicotine exposure diminished the adolescent nucleus accumbens dopamine response to 0.07 mg/kg nicotine i.v. However, dopamine responses to 0.105 mg/kg nicotine were unaffected by gestational nicotine treatment and were similar in both genders. Furthermore, in both female and male gestational nicotine and control groups, the dopamine response to nicotine (0.105) was the same as that observed to the lower dose of nicotine in gestational controls. Thus, in adolescent male and female Lewis rats, gestational nicotine exposure attenuated nucleus accumbens dopamine release to a maximally stimulative dose of nicotine. Unexpectedly, in female gestational controls cross fostering per se reduced nucleus accumbens dopamine secretion to 0.07 mg/kg nicotine. These investigations suggest that gestational nicotine exposure could modify the acute reinforcing effects of nicotine in adolescent rats, whereas early postnatal stressors, (e.g., cross-fostering) may affect nicotine-induced reinforcement in female but not male adolescents. Kane, V.B., Fu, Y., Matta, S.G. and Sharp, B.M. Gestational Nicotine Exposure Attenuates Nicotine-Stimulated Dopamine Release in the Nucleus Accumbens Shell of Adolescent Lewis Rats. JPET, 308(2), pp. 521-528, 2004.

Disproportionate Increase in the Up-regulation of the a6 Subunit nAChR During Long-term Self-administration of Nicotine

In male rats continually self-administering nicotine (approximately 1.5 mg free base/kg/day), Dr. Sharp and colleagues found a significant increase of nicotinic acetylcholine receptors (nAChRs) labeled by epibatidine (Epb) in 11 brain areas. A large increase of high affinity Epb binding sites was apparent in the ventral tegmentum/ substantia nigra, nucleus tractus solitarii, nucleus accumbens, thalamus/subthalamus, parietal cortex, hypothalamus, and amygdala. A smaller but significant up-regulation of high affinity Epb sites was seen in the piriform cortex, hippocampus, caudate/putamen, and cerebellar cortex. The up-regulation of nAChRs, shown by immunoadsorption and Western blotting, involved a4, a6, and b2 subunits. As a consequence of long-term self-administration of nicotine, the a6 immunoreactive (IR) binding of either labeled Epb or 125I-a-conotoxin MII increased to a much greater extent than did a4 or b2 IR binding of Epb. In addition, the b2 IR binding of Epb was consistently enhanced to a greater extent than was a4. These findings may reflect a larger surface membrane retention of a6-containing and, to some degree, b2-containing nAChRs compared with a4-containing nAChRs during long-term self-administration of nicotine. Parker, S.L, Fu, Y., McAllen, K., Luo, J., McIntosh, J.M., Lindstrom, J.M. and Sharp, B.M. Up-Regulation of Brain Nicotinic Acetylcholine Receptors in the Rat during Long-Term Self-Administration of Nicotine: Disproportionate Increase of the a6 Subunit. Mol Pharm, 65(3), pp. 611-622, 2004.

Morphine-Induced Pruritus Inhibited, and Analgesic Potency Enhanced, by the Kappa Opioid Receptor Agonist, U-50488H

Morphine is a potent analgesic used to treat moderate to severe pain. Though effective as an analgesic, morphine has side effects that limit its use. One side effect that can be especially severe is pruritus (itch), where morphine acts at central mu receptors to cause a maddening pruritus of the face and trunk. Dr. Ko and colleagues have found in monkeys that the kappa opioid receptor agonist, U-50488H, attenuated the scratching (an indication of pruritus) produced by morphine administration. Further, U-50488H enhanced the analgesic properties of morphine. These data suggest that a combination therapy of morphine and U-50488H may produce more analgesia with fewer side effects than morphine alone. Ko, M.C. et al., Activation of Kappa-Opioid Receptors Inhibits Pruritus Evoked by Subcutaneous or Intrathecal Administration of Morphine in Monkeys, JPET, 305, pp. 173-179, 2003.

Molecular Profiling of Midbrain Dopamine Regions in Cocaine Overdose Victims

Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in brain regions associated with drug reinforcement. To evaluate whether the alterations in gene expression in cocaine overdose victims are associated with specific dopamine populations in the midbrain, cDNA arrays and western blotting were used to compare gene and protein expression patterns between cocaine overdose victims and age-matched controls in the ventral tegmental area (VTA) and lateral substantia nigra. Scott Hemby and colleagues found significant up-regulation of numerous transcripts in the VTA, but not in the substantia nigra, of cocaine overdose victims. The up-regulated transcripts included several glutamate receptor transcripts (NMDAR1, GlurR2, GluR5, and KA2), and VTA-selective up-regulation of CREB protein was observed by western blot. The findings of these up-regulated mRNA and protein levels may be indicative of chronic cocaine use and/or cocaine overdose in humans. The observed changes may indicate alterations in the excitability of dopamine transmission underlying long-term biochemical and behavioral effects of cocaine. Tang, W-X., Fasulo, W.H., Mash, D.C., and Hemby, S.E. Molecular Profiling of Midbrain Dopamine Regions in Cocaine Overdose Victims. J. Neurochemistry, 85, pp. 911-924, 2003.

Homer1 Proteins and AMPA Receptors Modulate Cocaine-Induced Behavioral Plasticity

Homer proteins form functional assemblies in the excitatory postsynaptic density, and withdrawal from repeated cocaine administration reduces the expression of Homer1b/c in the nucleus accumbens. To determine if the reduction in Homer1b/c may be contributing to cocaine-induced behavioral sensitization, Dr. M.B. Ghasemzadeh and his research team at the Medical University of South Carolina infused antisense oligonucleotides over two weeks into the nucleus accumbens of rats to reduce Homer1 gene expression by approximately 35%. Infusion of antisense sequences (AS1 and AS2) caused a sensitization-like augmentation in the motor response to acute cocaine administration in naive rats. One of the sequences (AS1) also prevented the development of sensitization to repeated cocaine treatment, while AS2 was without effect. A panel of immunoblots for other proteins in the excitatory postsynaptic density revealed that AS1, but not AS2 reduced the level of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 protein. This posed the possibility that altered AMPA signaling may mediate the inhibitory effect of AS1 on the development of sensitization. To examine this possibility, rats were pretreated in the accumbens with drugs to block AMPA/kainate, N-methyl-d-aspartate, group 1 metabotropic glutamate or dopamine receptors prior to each daily injection of cocaine. Only AMPA/kainate receptor blockade prevented the development of behavioral sensitization to cocaine. These data indicate that the expression of behavioral sensitization arises in part from a reduction in Homer1 gene products in the accumbens, while the development of sensitization requires stimulation of AMPA/kainate receptors. Ghasemzadeh, M.B., Permenter, L.K., Lake, R., Worley, P.F., Kalivas, P.W. Homer1 Proteins and AMPA Receptors Modulate Cocaine-induced Behavioral Plasticity. Eur J. Neurosci.,18(6), pp. 1645-1651, September 2003.

Dopamine Neurons Release Transmitter via a Flickering Fusion Pore

It has been debated whether synaptic vesicles release all of their neurotransmitter into the synapse at once during a full fusion of the vesicular membrane with the neuron's outer membrane, or whether they "kiss-and-run" several times, releasing only part of their transmitter via transient fusion pores. A new study demonstrates that dopamine (DA) neuron synaptic vesicle fusion pores "flicker" (open and close) either once or multiple times in very rapid succession (4000 Hz), and each flicker (whether there is only one or several flickers per exocytic event) releases about 25-30% of vesicular DA. These researchers measured DA release from synaptic vesicles of cultured rat ventral tegmental area neurons using carbon fiber amperometry; this technique directly measures DA exocytosis with a time resolution 2-5 orders of magnitude greater than other techniques, and so was able, for the first time, to demonstrate the multiple flickering nature of DA release. The incidence of events with multiple flickers was decreased by a phorbol ester (protein kinase C (PKC) activator) and increased by staurosporine (kinase inhibitor), suggesting that this process is regulated by the PKC second messenger system. Thus, DA neurons regulate the amount of DA released by controlling the number of fusion pore flickers per exocytic event. This mode of exocytosis is a potential mechanism whereby neurons may rapidly re-use vesicles without undergoing the comparatively slow process of recycling. Staal, R.G.W., Mosharov, E.V. and Sulzer, D. Dopamine Neurons Release Transmitter via a Flickering Fusion Pore. Nature Neuroscience, published online 29 February 2004.

Marijuana Disrupted Signal Flow at Cortical Pyramidal Synapses -- The Entrypoint of Cognitive/Decision-Making Circuits

Marijuana affects cognitive functions, and is frequently abused by teenagers. Craving for drugs involves an interruption of the brain functions and a decision-making process. As an endogenous modulator system widely present in areas related to cognition, memory, emotion and reward, what role do cannabinoid receptors and the endocannabinoids play in cognition and decision-making processes? These processes rely on the function of cortical pyramidal cells that are responsible for functional connections between cortical areas, and to subcortical structures. Signal encoding at cortical synapses is the fundamental process that integrates afferent inputs and initiates coordination in the cognitive circuit network. Dr. Levine's recent work focuses on the importance of the endocannabinoid system in the fine-tuning of the cortical synapse-by-synapse information flow, to provide cellular basis of endogenous cannabinoid signaling in the regulation of neocortical function. He showed that activity of the pyramidal cell was controlled by distinct classes of the inhibitory GABAergic interneurons, which innervated functionally segregated domains on pyramidal cells and regulated timing of the action potential, the efficacy of excitatory inputs, and synchronous activity. These interneurons fire at high frequency in vivo and provide potent inhibition to pyramidal cells. Endogenous cannabinoid ligands are synthesized and released from pyramidal neurons with a high degree of spatial and temporal specificity, and act at least in part by feedback binding to receptors on the presynaptic terminals of interneurons to regulate their release of GABA, which in turn modulated signal processing at the pyramidal cell. Levine's lab demonstrated that this micro-feedback circuit is the structural basis of the depolarization-suppression of inhibition in cortical pyramidal cells, a cannabinoid-mediated mechanism of signal disinhibition that involved synaptic plasticity, originally demonstrated in the hippocampus and then in the cerebellum. Trettel, J. and Levine, E.S. Endocannabinoids Mediate Rapid Retrograde Signaling at Interneuron -- Pyramidal Neuron Synapses of the Neocortex. J. Neurophysiol, 89, pp. 2334-2338, 2003.

D1 Receptors Increase GluR1 Surface Expression in Cultured Nucleus Accumbens Neurons via PKA Activation

In the first study to examine AMPA receptor trafficking in neurons of the striatal complex, Dr. Marina Wolf found that brief incubation with a D1 agonist increased GluR1 surface expression in cultured NAc neurons (Chao et al., J Neurochem 83, 704-12, 2002). In the present study, she used an immunocytochemical method for selectively detecting newly externalized GluR1 to demonstrate that the D1 agonist SKF 81297 increased the rate of GluR1 externalization. This trafficking was blocked by a D1 receptor antagonist and by two different cell-permeable PKA inhibitors, KT5720 and RpcAMPS, and this effect was reversed in the presence of a PKA activator. Her previous work had shown that D1 receptor stimulation increased GluR1 phosphorylation at the PKA site (Chao et al., J Neurochem 81, 984-992, 2002). Together, their findings suggest that PKA phosphorylation of GluR1 is required for GluR1 externalization in response to D1 receptor stimulation. These results establish a direct mechanism by which D1 DA receptors, stimulated during psychostimulant administration, may influence glutamate neurotransmission and glutamate-dependent neuroplasticity. During repeated psychostimulant administration, inappropriate activation of this mechanism may lead to maladaptive plasticity in PFC, NAc and other regions that receive convergent DA and glutamate inputs. Ultimately, this may contribute to rewiring of motivational circuits and a transition to compulsive drug use. Mangiavacchi, S. and Wolf, M.E. D1 Dopamine Receptor Stimulation Increases the Rate of AMPA Receptor Insertion onto the Surface of Cultured Nucleus Accumbens Neurons through a Pathway Dependent on Protein Kinase A, J. Neurochem, 88, pp. 1261-1271, 2004.

Psychostimulant Sensitivity Requires PSD-95, a Key Regulator of Dopamine-Mediated Synaptic Plasticity

Chronic cocaine exposure leads to a long-lived escalation in psychomotor responses via a process called behavioral sensitization. Adaptive changes in the nucleus accumbens, and two of its most important afferents (the ventral tegmental area and cortical glutamatergic imputs) are important in this process. Recent work by the Caron laboratory has identified the synaptic scaffolding protein PSD-95 as being a key mediator in an important aspect of the underlying molecular changes. PSD-95 (as well as five other commonly altered genes) was identified using a microarray approach, and its function was tested using homologous recombination. At the synaptic level, enhanced LTP of the frontal cortico-accumbal glutamatergic synapses was correlated with decreased PSD-95 in cocaine-sensitized mice, as well as three mice lines mutant for differing monoamine transports (vesicular monoamine transporter, DA transporter, and NE transporter). In the cortico-accumbal synapses of mutant mice, the absence of PSD-95 leads to a "supersensitivity" to cocaine, and an "uncoupling" of glutamatergic transmissions from modulation by the dopamine system. This work illustrates a portion of the means by which drugs of abuse can usurp reward circuits by altering the cortical glutamatergic system. Furthermore since PSD-95 and LTP are also associated with learning and memory, this work provides solid evidence that the mechanism driving long-lasting, drug-induced behavioral plasticity may occur by using the same cellular machinery. Yao, W-D., Gainetdinov, R.R., Arbuckle, M.I., Sotnikova, T.D., Cyr, M., Beaulieu, J-M., Gonzalo, E.T., Grant, S.G.N. and Caron, M G. Identification of PSD-95 as a Regulator of Dopamine-Mediated Synaptic and Behavioral Plasticity. Neuron, 41, pp. 625-638, 2004.

Spatial Profiling with MALDI MS: Distribution of Neuropeptides within Single Neurons

The distribution of peptides and proteins within a neuron plays an important role in the functioning of those molecules. Currently, we do not know how different the molecular content of one region of a cell is from another region of the same cell. Through the NIDA Cutting Edge Basic Research Award (CEBRA), Dr. Sweedler and colleagues have developed protocols for subcellular analysis of peptide distribution in cell bodies and neuronal processes. The model system used in these studies was Aplysia californica. This sea slug has large neurons making it a good test bed for doing single cell analysis to see if current technology will allow us to distinguish peptide profiles from different regions of a single cell. One of the challenges the researchers faced is seawater surrounding the neurons is problematic for the mass spectrometry technology they were using to obtain peptide profiles. The research team was ultimately able to find conditions that are compatible with the technology and allowed them to preserve cell morphology and prevent neuropeptide redistribution. They are finding that profiles of peptides in specific neuronal processes and the cell bodies demonstrate a variety of differences that appear to be cell-specific. These developments will contribute to researchers' abilities to use this type of technology in higher order animal systems. Being able to profile peptides or proteins in a spatial context may ultimately help us understand similarities and differences between different neurons and indeed between different neuronal projections. Rubakhin, S.S., Greenough, W.T. and Sweedler, J.V. Anal Chem.,75(20), pp. 5374-5380, October 15, 2003.

Neuroimmunology and Drugs of Abuse

The recent J Neuroimmunol V. 247, issues 1-2, 2004 presents a number of NIDA publications focusing on drugs of abuse actions on neuroimmune activities. These include topics of delta-opioid activities and mechanisms (B. Sharp); evidence implicating cocaine as a possible risk factor for HIV infection (Tashkin et al.); how morphine influences SAIDS in a monkey model (Donohoe); mechanisms of cannabinoids actions on diseases in mice (Klein et al.); immune cell activity during the initial stages of withdrawal from chronic exposure to cocaine or morphine (Bayer et al.); cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures (Peterson et al.); and cannabinoid-mediated exacerbation of brain infection (Cabral et al.). It also has other drug studies by non-NIDA supported scientists.


Index

Research Findings

Program Activities

Extramural Policy and Review Activities

Congressional Affairs

International Activities

Meetings and Conferences

Media and Education Activities

Planned Meetings

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Staff Highlights

Grantee Honors



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