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Chapter 12 Nervous Tissue Lecture Outline Principles of Human Anatomy and Physiology, 11e 1 INTRODUCTION  The nervous system, along with the endocrine system, helps to keep controlled conditions within limits that maintain health and helps to maintain homeostasis.  The nervous system is responsible for all our behaviors, memories, and movements.  The branch of medical science that deals with the normal functioning and disorders of the nervous system is called neurology. 2 Chapter 12 Nervous Tissue  Controls and integrates all body activities within limits that maintain life  Three basic functions  sensing changes with sensory receptors    fullness of stomach or sun on your face interpreting and remembering those changes reacting to those changes with effectors   muscular contractions glandular secretions 3 Major Structures of the Nervous System  Brain, cranial nerves, spinal cord, spinal nerves, ganglia, enteric plexuses and sensory receptors 4 Structures of the Nervous System - Overview  Twelve pairs of cranial nerves emerge from the base of the brain through foramina of the skull.  A nerve is a bundle of hundreds or thousands of axons, each of which courses along a defined path and serves a specific region of the body.  The spinal cord connects to the brain through the foramen magnum of the skull and is encircled by the bones of the vertebral column.  Thirty-one pairs of spinal nerves emerge from the spinal cord, each serving a specific region of the body.  Ganglia, located outside the brain and spinal cord, are small masses of nervous tissue, containing primarily cell bodies of neurons.  Enteric plexuses help regulate the digestive system.  Sensory receptors are either parts of neurons or specialized cells that monitor changes in the internal or external environment. 5 12 pair of cranial nerves 6 Cranial Nerves 7 Cranial Nerve Names On Olfactory CN I Old Optical CN II Olympus’ Occulomotor CN III Towering Trochlear CN IV Top Trigeminal CN V A Abducens CN VI Fat Facial CN VII Vivacous Vestibulocochlear CN VIII Goat Glossopharyngeal CN IX Victomized Vagus CN X A Accessory CN XI Hat Hypoglossal CN XII 8 Functions of the Nervous Systems  The sensory function of the nervous system is to sense changes in the internal and external environment through sensory receptors.  Sensory (afferent) neurons serve this function.  The integrative function is to analyze the sensory information, store some aspects, and make decisions regarding appropriate behaviors.  Association or interneurons serve this function.  The motor function is to respond to stimuli by initiating action.  Motor(efferent) neurons serve this function. 9 Nervous System Divisions  Central nervous system (CNS)  consists of the brain and spinal cord  Peripheral nervous system (PNS)   consists of cranial and spinal nerves that contain both sensory and motor fibers connects CNS to muscles, glands & all sensory receptors 10 Subdivisions of the PNS  Somatic (voluntary) nervous system (SNS)  neurons from cutaneous and special sensory receptors to the CNS  motor neurons to skeletal muscle tissue  Autonomic (involuntary) nervous systems  sensory neurons from visceral organs to CNS  motor neurons to smooth & cardiac muscle and glands   sympathetic division (speeds up heart rate) parasympathetic division (slow down heart rate)  Enteric nervous system (ENS)  involuntary sensory & motor neurons control GI tract  neurons function independently of ANS & CNS 11 Organization of the Nervous System  CNS is brain and spinal cord  PNS is everything else 12 Enteric NS  The enteric nervous system (ENS) consists of neurons in enteric plexuses that extend the length of the GI tract.   Many neurons of the enteric plexuses function independently of the ANS and CNS. Sensory neurons of the ENS monitor chemical changes within the GI tract and stretching of its walls, whereas enteric motor neurons govern contraction of GI tract organs, and activity of the GI tract endocrine cells. 13 Neuronal Structure & Function 14 Neurons  Functional unit of nervous system  Have capacity to produce action potentials electrical excitability  Cell body  single nucleus with prominent nucleolus  Nissl bodies (chromatophilic substance)  rough ER & free ribosomes for protein synthesis  neurofilaments give cell shape and support  microtubules move material inside cell  lipofuscin pigment clumps (harmless aging)  Cell processes = dendrites & axons  15 Parts of a Neuron Neuroglial cells Nucleus with Nucleolus Axons or Dendrites Cell body 16 Rat Neuron 17 18 Cell membrane  The dendrites are the receiving or input portions of a neuron.  The axon conducts nerve impulses from the neuron to the dendrites or cell body of another neuron or to an effector organ of the body (muscle or gland). 19 Dendrites  Conducts impulses towards the cell body  Typically short, highly branched & unmyelinated  Surfaces specialized for contact with other neurons  Contains neurofibrils & Nissl bodies 20 Axons  Conduct impulses away      from cell body Long, thin cylindrical process of cell Arises at axon hillock Impulses arise from initial segment (trigger zone) Side branches (collaterals) end in fine processes called axon terminals Swollen tips called synaptic end bulbs contain vesicles filled with neurotransmitters 21 Axonal Transport  Cell body is location for most protein synthesis  neurotransmitters & repair proteins  Axonal transport system moves substances  slow axonal flow    movement in one direction only -- away from cell body movement at 1-5 mm per day fast axonal flow     moves organelles & materials along surface of microtubules at 200-400 mm per day transports in either direction for use or for recycling in cell body 22 Axonal Transport & Disease  Fast axonal transport route by which toxins or pathogens reach neuron cell bodies   tetanus (Clostridium tetani bacteria) disrupts motor neurons causing painful muscle spasms  Bacteria enter the body through a laceration or puncture injury  more serious if wound is in head or neck because of shorter transit time 23 Diversity in Neurons  Both structural and functional features are used to classify the various neurons in the body.  On the basis of the number of processes extending from the cell body (structure), neurons are classified as multipolar, biopolar, and unipolar (Figure 12.4).  Most neurons in the body are interneurons and are often named for the histologist who first described them or for an aspect of their shape or appearance. Examples are Purkinje cells (Figure 12.5a) or Renshaw cells (Figure 12.5b). 24 Structural Classification of Neurons  Based on number of processes found on cell body  multipolar = several dendrites & one axon  most common cell type  bipolar neurons = one main dendrite & one axon  found in retina, inner ear & olfactory  unipolar neurons = one process only(develops from a bipolar)  are always sensory neurons 25 Functional Classification of Neurons  Sensory (afferent) neurons  transport sensory information from skin, muscles, joints, sense organs & viscera to CNS  Motor (efferent) neurons  send motor nerve impulses to muscles & glands  Interneurons (association) neurons   connect sensory to motor neurons 90% of neurons in the body 26 Association or Interneurons 27 Neuroglial Cells  Half of the volume of the CNS  Smaller cells than neurons  50X more numerous  Cells can divide  rapid mitosis in tumor formation (gliomas)  4 cell types in CNS  astrocytes, oligodendrocytes, microglia & ependymal  2 cell types in PNS  schwann and satellite cells 28 Astrocytes  Star-shaped cells  Form blood-brain barrier by covering blood capillaries  Metabolize neurotransmitters  Regulate K+ balance  Provide structural support 29 Microglia  Small cells found near blood vessels  Phagocytic role -clear away dead cells  Derived from cells that also gave rise to macrophages & monocytes 30 Ependymal cells  Form epithelial membrane lining cerebral cavities & central canal  Produce cerebrospinal fluid (CSF) 31 Satellite Cells  Flat cells surrounding neuronal cell bodies in peripheral ganglia  Support neurons in the PNS ganglia 32 Oligodendrocytes  Most common glial cell type  Each forms myelin sheath around more than one axons in CNS  Analogous to Schwann cells of PNS 33 Myelination  A multilayered lipid and protein covering called the myelin sheath and produced by Schwann cells and oligodendrocytes surrounds the axons of most neurons (Figure 12.8a).  The sheath electrically insulates the axon and increases the speed of nerve impulse conduction. 34 Schwann Cell  Cells encircling PNS axons  Each cell produces part of the myelin sheath surrounding an axon in the PNS 35 Axon Coverings in PNS  All axons surrounded by a lipid & protein covering (myelin sheath) produced by Schwann cells  Neurilemma is cytoplasm & nucleus of Schwann cell  gaps called nodes of Ranvier  Myelinated fibers appear white  jelly-roll like wrappings made of lipoprotein = myelin  acts as electrical insulator  speeds conduction of nerve impulses  Unmyelinated fibers  slow, small diameter fibers  only surrounded by neurilemma but no myelin sheath wrapping 36 Myelination in PNS  Schwann cells myelinate (wrap around) axons in the PNS during fetal development  Schwann cell cytoplasm & nucleus forms outermost layer of neurolemma with inner portion being the myelin sheath  Tube guides growing axons that are repairing themselves 37 Myelination in the CNS  Oligodendrocytes myelinate axons in the CNS  Broad, flat cell processes wrap about CNS axons, but the cell bodies do not surround the axons  No neurilemma is formed  Little regrowth after injury is possible due to the lack of a distinct tube or neurilemma 38 Gray and White Matter  White matter = myelinated processes (white in color)  Gray matter = nerve cell bodies, dendrites, axon terminals, bundles of unmyelinated axons and neuroglia (gray color)   In the spinal cord = gray matter forms an H-shaped inner core surrounded by white matter In the brain = a thin outer shell of gray matter covers the surface & is found in clusters called nuclei inside the CNS  A nucleus is a mass of nerve cell bodies and dendrites 39 inside the CNS. Electrical Signals in Neurons  Neurons are electrically excitable due to the voltage difference across their membrane  Communicate with 2 types of electric signals   action potentials that can travel long distances graded potentials that are local membrane changes only  In living cells, a flow of ions occurs through ion channels in the cell membrane 40 Two Types of Ion Channels  Leakage (nongated) channels are always open    nerve cells have more K+ than Na+ leakage channels as a result, membrane permeability to K+ is higher explains resting membrane potential of -70mV in nerve tissue  Gated channels open and close in response to a stimulus  results in neuron excitability 41 Ion Channels  Gated ion channels respond to voltage changes, ligands (chemicals), and mechanical pressure.    Voltage-gated channels respond to a direct change in the membrane potential (Figure 12.10a). Ligand-gated channels respond to a specific chemical stimulus (Figure 12.10b). Mechanically gated ion channels respond to mechanical vibration or pressure. 42 Gated Ion Channels 43 Resting Membrane Potential  Negative ions along inside of cell membrane & positive ions along outside   potential energy difference at rest is -70 mV cell is “polarized”  Resting potential exists because  concentration of ions different inside & outside  extracellular fluid rich in Na+ and Cl  cytosol full of K+, organic phosphate & amino acids  membrane permeability differs for Na+ and K+  50-100 greater permeability for K+  inward flow of Na+ can’t keep up with outward flow of K+  Na+/K+ pump removes Na+ as fast as it leaks in 44 45 Graded Potentials  Small deviations from resting potential of -70mV   hyperpolarization = membrane has become more negative depolarization = membrane has become more positive  The signals are graded, meaning they vary in amplitude (size), depending on the strength of the stimulus and localized.  Graded potentials occur most often in the dendrites and cell body of a neuron. 46 How do Graded Potentials Arise?  Source of stimuli   mechanical stimulation of membranes with mechanical gated ion channels (pressure) chemical stimulation of membranes with ligand gated ion channels (neurotransmitter)  Graded/postsynaptic/receptor or generator potential   ions flow through ion channels and change membrane potential locally amount of change varies with strength of stimuli  Flow of current (ions) is local change only 47 Generation of an Action Potential  An action potential (AP) or impulse is a sequence of rapidly occurring events that decrease and eventually reverse the membrane potential (depolarization) and then restore it to the resting state (repolarization).  During an action potential, voltage-gated Na+ and K+ channels open in sequence (Figure 12.13).  According to the all-or-none principle, if a stimulus reaches threshold, the action potential is always the same.  A stronger stimulus will not cause a larger impulse. 48 Action Potential  Series of rapidly occurring events that change and then restore the membrane potential of a cell to its resting state  Ion channels open, Na+ rushes in (depolarization), K+ rushes out (repolarization)  All-or-none principal = with stimulation, either happens one specific way or not at all (lasts 1/1000 of a second)  Travels (spreads) over surface of cell without dying out 49 Depolarizing Phase of Action Potential  Chemical or mechanical stimulus caused a graded potential to reach at least (-55mV or threshold)  Voltage-gated Na+ channels open & Na+ rushes into cell     in resting membrane, inactivation gate of sodium channel is open & activation gate is closed (Na+ can not get in) when threshold (-55mV) is reached, both open & Na+ enters inactivation gate closes again in few ten-thousandths of second only a total of 20,000 Na+ actually enter the cell, but they change the membrane potential considerably(up to +30mV)  Positive feedback process 50 Repolarizing Phase of Action Potential  When threshold potential of      -55mV is reached, voltage-gated K+ channels open K+ channel opening is much slower than Na+ channel opening which caused depolarization When K+ channels finally do open, the Na+ channels have already closed (Na+ inflow stops) K+ outflow returns membrane potential to -70mV If enough K+ leaves the cell, it will reach a -90mV membrane potential and enter the after-hyperpolarizing phase K+ channels close and the membrane potential returns to the resting potential of -70mV 51 Refractory Period of Action Potential  Period of time during which neuron can not generate another action potential  Absolute refractory period    even very strong stimulus will not begin another AP inactivated Na+ channels must return to the resting state before they can be reopened large fibers have absolute refractory period of 0.4 msec and up to 1000 impulses per second are possible  Relative refractory period  a suprathreshold stimulus will be able to start an AP  K+ channels are still open, but Na+ channels have closed 52 The Action Potential: Summarized  Resting membrane potential is -70mV  Depolarization is the change from 70mV to +30 mV  Repolarization is the reversal from +30 mV back to -70 mV) 53 Local Anesthetics  Local anesthetics and certain neurotoxins   Prevent opening of voltage-gated Na+ channels Nerve impulses cannot pass the anesthetized region Examples:  Novocaine and lidocaine 54 Propagation of Action Potential  An action potential spreads (propagates) over the surface of the axon membrane   as Na+ flows into the cell during depolarization, the voltage of adjacent areas is effected and their voltage-gated Na+ channels open self-propagating along the membrane  The traveling action potential is called a nerve impulse 55 Continuous versus Saltatory Conduction  Continuous conduction (unmyelinated fibers)  step-by-step depolarization of each portion of the length of the axolemma  Saltatory conduction   depolarization only at nodes of Ranvier where there is a high density of voltage-gated ion channels current carried by ions flows through extracellular fluid from node to node 56 Saltatory Conduction  Nerve impulse conduction in which the impulse jumps from node to node 57 Speed of Impulse Propagation  The propagation speed of a nerve impulse is not related to stimulus strength.  larger, myelinated fibers conduct impulses faster due to size & saltatory conduction  Fiber types  A fibers largest (5-20 microns & 130 m/sec)   B fibers medium (2-3 microns & 15 m/sec)   myelinated somatic sensory & motor to skeletal muscle myelinated visceral sensory & autonomic preganglionic C fibers smallest (.5-1.5 microns & 2 m/sec)  unmyelinated sensory & autonomic motor 58 Encoding of Stimulus Intensity  How do we differentiate a light touch from a firmer touch?  frequency of impulses   firm pressure generates impulses at a higher frequency number of sensory neurons activated  firm pressure stimulates more neurons than does a light touch 59 Action Potentials in Nerve and Muscle  Entire muscle cell membrane versus only the axon of the neuron is involved  Resting membrane potential   nerve is -70mV skeletal & cardiac muscle is closer to -90mV  Duration   nerve impulse is 1/2 to 2 msec muscle action potential lasts 1-5 msec for skeletal & 10-300msec for cardiac & smooth  Fastest nerve conduction velocity is 18 times faster than velocity over skeletal muscle fiber 60 SIGNAL TRANSMISSION AT SYNAPSES  A synapse is the functional junction between one neuron and another or between a neuron and an effector such as a muscle or gland. 61 Signal Transmission at Synapses  2 Types of synapses  electrical    ionic current spreads to next cell through gap junctions faster, two-way transmission & capable of synchronizing groups of neurons chemical  one-way information transfer from a presynaptic neuron to a postsynaptic neuron  axodendritic -- from axon to dendrite  axosomatic -- from axon to cell body  axoaxonic -- from axon to axon 62 63 Chemical Synapses  Action potential reaches end bulb     and voltage-gated Ca+ 2 channels open Ca+2 flows inward triggering release of neurotransmitter Neurotransmitter crosses synaptic cleft & binding to ligand-gated receptors  the more neurotransmitter released the greater the change in potential of the postsynaptic cell Synaptic delay is 0.5 msec One-way information transfer 64 Excitatory & Inhibitory Potentials  The effect of a neurotransmitter can be either excitatory or inhibitory  a depolarizing postsynaptic potential is called an EPSP    it results from the opening of ligand-gated Na+ channels the postsynaptic cell is more likely to reach threshold an inhibitory postsynaptic potential is called an IPSP    it results from the opening of ligand-gated Cl- or K+ channels it causes the postsynaptic cell to become more negative or hyperpolarized the postsynaptic cell is less likely to reach threshold 65 Removal of Neurotransmitter  Diffusion  move down concentration gradient  Enzymatic degradation  acetylcholinesterase  Uptake by neurons or glia cells   neurotransmitter transporters Prozac = serotonin reuptake inhibitor 66 Three Possible Responses  Small EPSP occurs  potential reaches -56 mV only  An impulse is generated   threshold was reached membrane potential of at least -55 mV  IPSP occurs   membrane hyperpolarized potential drops below -70 mV 67 Comparison of Graded & Action Potentials  Origin   GPs arise on dendrites and cell bodies APs arise only at trigger zone on axon hillock  Types of Channels   AP is produced by voltage-gated ion channels GP is produced by ligand or mechanicallygated channels  Conduction   GPs are localized (not propagated) APs conduct over the surface of the axon 68 Comparison of Graded & Action Potentials  Amplitude   amplitude of the AP is constant (all-or-none) graded potentials vary depending upon stimulus  Duration  The duration of the GP is as long as the stimulus lasts  Refractory period  The AP has a refractory period due to the nature of the voltage-gated channels, and the GP has none. 69 Summation  If several presynaptic end bulbs release their neurotransmitter at about the same time, the combined effect may generate a nerve impulse due to summation  Summation may be spatial or temporal. 70 Spatial Summation  Summation of effects of neurotransmitters released from several end bulbs onto one neuron 71 Temporal Summation  Summation of effect of neurotransmitters released from 2 or more firings of the same end bulb in rapid succession onto a second neuron 72 Summation  The postsynaptic neuron is an integrator, receiving and integrating signals, then responding.  If the excitatory effect is greater than the inhibitory effect but less that the threshold level of stimulation, the result is a subthreshold EPSP, making it easier to generate a nerve impulse.  If the excitatory effect is greater than the inhibitory effect and reaches or surpasses the threshold level of stimulation, the result is a threshold or suprathreshold EPSP and a nerve impulse.  If the inhibitory effect is greater than the excitatory effect, the membrane hyperpolarizes (IPSP) with 73 failure to produce a nerve impulse. Neurotransmitters  Both excitatory and inhibitory neurotransmitters are present in the CNS and PNS; the same neurotransmitter may be excitatory in some locations and inhibitory in others.  Important neurotransmitters include acetylcholine, glutamate, aspartate, gamma aminobutyric acid, glycine, norepinephrine, epinephrine, and dopamine. 74 Neurotransmitter Effects  Neurotransmitter effects can be modified     synthesis can be stimulated or inhibited release can be blocked or enhanced removal can be stimulated or blocked receptor site can be blocked or activated  Agonist  anything that enhances a transmitters effects  Antagonist  anything that blocks the action of a neurotranmitter 75 Small-Molecule Neurotransmitters  Acetylcholine (ACh)    released by many PNS neurons & some CNS excitatory on NMJ but inhibitory at others inactivated by acetylcholinesterase  Amino Acids   glutamate released by nearly all excitatory neurons in the brain ---- inactivated by glutamate specific transporters GABA is inhibitory neurotransmitter for 1/3 of all brain synapses (Valium is a GABA agonist -enhancing its inhibitory effect) 76 Small-Molecule Neurotransmitters  Biogenic Amines  modified amino acids (tyrosine)     norepinephrine -- regulates mood, dreaming, awakening from deep sleep dopamine -- regulating skeletal muscle tone serotonin -- control of mood, temperature regulation, & induction of sleep removed from synapse & recycled or destroyed by enzymes (monoamine oxidase or catechol-0-methyltransferase) 77 Small-Molecule Neurotransmitters  ATP and other purines (ADP, AMP & adenosine)   excitatory in both CNS & PNS released with other neurotransmitters (ACh & NE)  Gases (nitric oxide or NO)   formed from amino acid arginine by an enzyme formed on demand and acts immediately    diffuses out of cell that produced it to affect neighboring cells may play a role in memory & learning first recognized as vasodilator that helps lower blood pressure 78 Neuropeptides  3-40 amino acids linked by peptide bonds  Substance P -- enhances our perception of pain  Pain relief  enkephalins -- pain-relieving effect by blocking the release of substance P (bind to morphine receptors in the central nervous system and have opioid properties)  acupuncture may produce loss of pain sensation because of release of opioids-like substances such as endorphins or dynorphins 79 Strychnine Poisoning  In spinal cord, Renshaw cells normally release an inhibitory neurotransmitter (glycine) onto motor neurons preventing excessive muscle contraction  Strychnine binds to and blocks glycine receptors in the spinal cord  Massive tetanic contractions of all skeletal muscles are produced  when the diaphragm contracts & remains contracted, breathing can not occur 80 Neuronal Circuits  Neuronal pools are organized into circuits (neural networks.) These include simple series, diverging, converging, reverberating, and parallel after-discharge circuits (Figure 12.18 a-d).  A neuronal network may contain thousands or even millions of neurons.  Neuronal circuits are involved in many important activities    breathing short-term memory waking up 81 Neuronal Circuits  Diverging -- single cell stimulates many others  Converging -- one cell stimulated by many others  Reverberating -- impulses from later cells repeatedly stimulate early cells in the circuit (short-term memory)  Parallel-after-discharge -- single cell stimulates a group of cells that all stimulate a common postsynaptic cell (math82 problems) Regeneration & Repair  Plasticity maintained throughout life    sprouting of new dendrites synthesis of new proteins changes in synaptic contacts with other neurons  Limited ability for regeneration (repair)   PNS can repair damaged dendrites or axons CNS no repairs are possible 83 Damage and Repair in the Peripheral Nervous System  When there is damage to an axon, usually there are changes, called chromatolysis, which occur in the cell body of the affected cell; this causes swelling of the cell body and peaks between 10 and 20 days after injury.  By the third to fifth day, degeneration of the distal portion of the neuronal process and myelin sheath (Wallerian degeneration) occurs; afterward, macrophages phagocytize the remains.  Retrograde degeneration of the proximal portion of the fiber extends only to the first neurofibral node.  Regeneration follows chromatolysis; synthesis of RNA and protein accelerates, favoring rebuilding of the axon and often taking several months. 84 Repair within the PNS  Axons & dendrites may be repaired if    neuron cell body remains intact schwann cells remain active and form a tube scar tissue does not form too rapidly  Chromatolysis  24-48 hours after injury, Nissl bodies break up into fine granular masses 85 Repair within the PNS  By 3-5 days,  wallerian degeneration occurs (breakdown of axon & myelin sheath distal to injury)  retrograde degeneration occurs back one node  Within several months, regeneration occurs   neurolemma on each side of injury repairs tube (schwann cell mitosis) axonal buds grow down the tube to reconnect (1.5 mm per day) 86 Neurogenesis in the CNS  Formation of new neurons from stem cells was not thought to occur in humans   1992 a growth factor was found that stimulates adult mice brain cells to multiply 1998 new neurons found to form within adult human hippocampus (area important for learning)  There is a lack of neurogenesis in other regions of the brain and spinal cord.  Factors preventing neurogenesis in CNS  inhibition by neuroglial cells, absence of growth stimulating factors, lack of neurolemmas, and rapid formation of scar tissue 87 Multiple Sclerosis (MS)  Autoimmune disorder causing destruction of myelin sheaths in CNS     sheaths becomes scars or plaques 1/2 million people in the United States appears between ages 20 and 40 females twice as often as males  Symptoms include muscular weakness, abnormal sensations or double vision  Remissions & relapses result in progressive, cumulative loss of function 88 Epilepsy  The second most common neurological disorder  affects 1% of population  Characterized by short, recurrent attacks initiated by electrical discharges in the brain    lights, noise, or smells may be sensed skeletal muscles may contract involuntarily loss of consciousness  Epilepsy has many causes, including;  brain damage at birth, metabolic disturbances, infections, toxins, vascular disturbances, head injuries, and tumors 89 end 90
 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
									 
                                             
                                             
                                             
                                             
                                             
                                             
                                             
                                             
                                             
                                             
                                            