Visual apparatus Oculus et structurae pertinentes

Visual apparatusOculus et structurae pertinentes

Morfology and embryology

Odilo Redon

Orbita

Shape of 4-sided pyramid falled backsideBony marginsaditus x apex10 openingsm. orbitalis Mülleri – smooth muscle in

fissura orbitalis inferiorcontent: eye ball, muscles, adipose tissue

and accessory organs

Orbita – bony walls

Orbita – bony walls

Surrounding structures:medially: cellulae ethmoidales (behind thin

lamina orbitalis o.e.)caudally: sinus maxillariscranially: fossa cerebri anteriordorsally: sinus cavernosus + fossa

pterygopalatina

Visual apparatus

Eye ball = Bulbus oculiAccessory apparatus = Structurae

accessoriae/pertinentes oculi Topography - regio orbitalisDevelopment of eye apparatus

Eye ball

tunica fibrosa (externa)

tunica vasculosa (media)

tunica interna (nervosa)

Vitreous body + lens cristallina

Eye ball

polus anterior, posterior

equator x meriadiani axis bulbi externus,

internus axis opticus (= „linea

visus“)

Tunica fibrosa (externa)

scleracornea

Tunica fibrosa (externa)Sclera

Thick tissue (= reticulum trabeculare), colagenous fibers, fibroblasts, basic substance

lamina episcleralis, substantia propria, lamina fusca lamina cribrosa (entrance of n. II.) 5/6 of surface, ø 2,2 cm sinus venosus sclerae (canalis Schlemmi s. Lauthi) sulcus sclerae – sclerocorneal junction = limbus corneae

(angulus sclerocornealis)

Tunica fibrosa (externa)Cornea

Totally translucent, w/o vessels limbus, vertex 5 layers

– epithelium anterius cornae (multi l. cuboid)– lamina limitans anterior (Bowmann membrane)– substantia propria corneae– lamina limitans posterior (Descement membrane)– epithelium posterius corneae („endotelium“)

11 x 12 mm – fyziological astigmatismus

Tunica vasculosa (media) = Uvea

choroid (choroidea)Ciliary body (corpus ciliare)iris (iris)

Tunica vasculosa (media) Choroidea

lamina suprachoroidea (= lamina fusca sclerae) spatium perichoroideum lamina vasculosa (choroideal stroma)

– Big vessels, tissue, smooth muscle cells, nerves lamina choroidocapillaris

– capillaries lamina basalis = Bruch membrane

– BM pigment epitelium and capillaries + tissue

Tunica vasculosa (media) ciliary body = Corpus ciliare

Shape of annulus, section of triangle

processus + plicae ciliares

orbiculus (outer part), corona (inner part)

smooth musculus ciliaris– fibrae meridionales,

radiales, circulares, longitudinales

Tunica vasculosa (media) ciliary body = Corpus ciliare stroma

– m. ciliaris: parasympaticus akomodation look close

(look remote maintains plasticity of uvea)– Capillaries and nerves supplying muscle

Epitelial cover – production of humor aquosus– BL – continuation of Bruchs membrane– pigment epitelium – (from pigment epitelium of retina)– Cilliary canal– Non pigmented epithelium (from sensory epithelium of

retina)– BL– fibrae zonulares – fixate lens

Tunica vasculosa (media)Iris

Shape of annulus, flat Function of shutter margo ciliaris (outer), m. pupillaris (inner) pupilla (= pupil) anulus iridis major + minor (contain circulus arteriosus

iridis major + minor) m. sphincter pupillae (parasymp.) – miosis (circular) m. dilatator pupillae (symp.) – mydriasis (fanwise)

Tunica vasculosa (media) Iris

plicae iridis, stroma iridis Anterior pole

– Does not have epithelial lining (stratum limitans anterius)– fibroblasts and melanocytes (color)– plica radians = serrated line – remnant of membrana

pupillaris Wachendorfi Posterior pole

– Two layers of pigment epithelium– Inner pigment– Outer myoepitelial

• m. sphincter pupillae• m. dilatator pupillae

Lens crystallina = Lens

polus anterior, posterior axis, equator, radii (sutures in Y shape and reversed

Y) capsula lentis substantia lentis – cortex, nucleus zonula ciliaris Zinni

– fibrae zonulares

– spatia zonularia

Gray cataracta - prosthesis

Lens crystallina (lens)

transparent biconvex w/o vessels capsula – similar to basal lamina Lens epithelium – single layer cuboid

– Only on anterior side of lens Lens matter

– cortical – contains elongated cells (fibers) with organels and nucleus

– nuclear – cellular fibers w/o organles and nucleus– Cells contain specific proteins (filensin, crystallins)

Acommodation

Focusing on close distance– Contraction of m. ciliaris

– fibrae zonulares relaxing

– Lens forms ball

– Together with contraction of m. sphincter pupillae (= miosis)

Focusing on remote distance– Tonus of vessels maintains fibrae zonulares extended

– Lens is flattened

– Contraction of m. dilatator pupillae (= mydriasis)

Vitreous body = Corpus vitreum

membrana, stroma, humor vitreus Composed of 99% water Hyaluronic acid, kolagen fibers cells – hyalocytes – only during development ! Does not regenerate ! – in case of injury it flows

out – exchanged by chamber fluid canalis hyaloideus Cloqueti – remnant of fetal

arteria hylaloidea fossa hyaloidea Maintains inner eyeball pressure, pushes retina

Chamber fluid= Humor aquosus

Produced by ciliary body Reabsorbed in angulus iridocornealis 0,2-0,3 ml translucent, watery fluid Daily produced cca 3 ml composition: 0,7-1,2 % NaCl, traces of urea and

glucose (0,1%), no proteins Serves as lymph Intraocular pressure 14-17 mmHg

Intraocular pressure pressure on retina glaucoma (= glaukom)

Eyeball chambers = Camerae bulbi

Vitreal chamber (camera postrema s. vitrea)– Between ciliary body, lens and retina– Contains vitreous body– spatium retrozonulare

posterior chamber (camera posterior)– Between iris, lens and ciliary body– Contains and produces humor aquosus

Anterior chamber (camera anterior)– Between cornea and iris– angulus iridocornealis– Contains and reabsorps humor aquosus

Iridocorneal angle= angulus iridocornealis

At the sclerocorneal junction

Trabecular frame of the back side = spatia anguli i.c. = Fontana spaces

Not connected with Schlemm canal

Resorption of humor aquosus

Maintenance of intraocular pressure

!!! No parasympaticolytics in glaucoma !!!

OCT

Optical coherent tomograp

h

measurement of light

reflection

Tunica interna (nervosa)= Retina

pars caeca – pars iridica– pars ciliaris

ora serratapars optica – 11 layers

– pigment part– Sensory part

Tunica interna (nervosa)Retina – pigment part

stratum pigmentosum Single layer cuboid epithelium cells (pigmentocytus) connected by tight junction Apical part contains melanin granules Surrounds external segments of sensory cells interfotoreceptor matrix

Cell nutrition, fotopigment rejuvenation, degradation of membranous discs

Tunica interna (nervosa) Retina – sensory part

Light recepting neurons– Rods and cones

Conduction neurons– Bipolar and ganglionic cells

Association neurons– Horizontal and amacrine cells

Supportive cells (glia)– Müllers cells

Tunica interna (nervosa) Retina – sensory part

discus n. optici (= blind spot) – No light perceiving elements

excavatio disci

macula lutea (= yellow spot) – higher layers to the side– Sharpest vision

– fovea centralis (100.000 cones) foveola (2500 cones)

Tunica sensoria (interna)Rods = Neuron bacilliferum rod = bacillum retinae synaptic disc (discus membranaceus) axon nucleus Inner segment

– GA, ER, MIT; synthesis of ATP and rhodopsin

Outer segment (segmentum externum)– Membranous discs with fotopigment

– migrate externally till separation

black-white vision

Tunica sensoria (interna)Cones = Neuron coniferum

rod = conus retinae synaptic pod (pes terminalis) fotopigment is iodopsin External segment

– Membranous discs with fotopigment• Communicate with around

Color vision – three types of rods – according to wave length– „blue“ – 420 nm – type S– „green“ – 535 nm – type M– „red“ – 565 nm – type L

Tunica sensoria (interna)conduction neurons

Bipolar cells (Neuron bipolare)– Staminate bipolare cells (n.b. bacillotopicum)

– Cony bipolar cells (n.b. conotopicum) • Dwarfy cells (n.b.c. nanum) x diffuse cells (n.b.c. diffusum)

– contact with ganglionic cells

Ganglionic cells (N. ganglionare multipolare)– Diffuse type (n.g.m. umbelliforme) – connects more bipolar cells

– Dwarfy type (n.g.m. nanum) – connects to dwarfy bipolar cell

– Their axons form nervus opticus

Tunica sensoria (interna)Association neurons

Have only axonal extensions – both directionHorizontal cells (N. horizontale)

– Connection with rods and cones

Amacrine cells (N. amacrinum)– Connection with bipolar and ganglionic cells

Modification and synchro of signal

Tunica sensoria (interna)supporting cells

Müllers cells (Gliocytus radialis)– macroglia– processus radiales– Have their own BL = membrana limitans

interna– zonulae adherentes with rods and cones

• = membrana limitans externa

Tunica sensoria (interna)Vrstvy zrakové části sítnice

celkem 11 vrstev

!!! neděste se !!!

Tunica sensoria (interna)layers of visual part of retina

stratum pigmentosum (1.) stratum nervosum (2.-10.)

– stratum segmentorum externorum et internorum(2.)– stratum limitans externum (3.)– stratum nucleare externum (4.)– stratum plexiforme externum (5.)– stratum nucleare internum (6.)– stratum plexiforme internum (7.)– stratum ganglionicum (8.)– stratum neurofibrarum (9.)– stratum limitans internum (10.)

Tunica sensoria (interna)Specific places of retina

ora serrata – termination of sensory epithelium pars optica – 10 layers

– discus n. optici /formerly papilla/ (= blind spot) – place of nerve separation

• No light detecting elements

• excavatio disci

– macula lutea (= yellow spot) – higher layers bent to the side, sharpest vision

• fovea centralis (100.000 cones) – only cones

– Higher layers bent side

– Sharpest vision

foveola (2500 cones)

OCT

Optical coherent

tomograph

measurement of light

reflextion

OCT

OCT

Retinal dystopia

Arterial supply of eye

a. carotis interna a. ophthalmica aa. ciliares posteriores breves choroidaa. ciliares posteriores longae (24) corpus

ciliare + irisaa. musculares aa. ciliares ant., aa.

episclerales, aa. conjuctivales lat.a. centralis retinae retinaa. lacrimalis aa. palpebrales lat.aa. palpebrales med. aa. conjuctivales med.

Vasa sanguinea retinae– eye backside (fundus oculi)

a. centralis retinae arterioles

a. temporalis sup.+ inf. a. nasalis sup.+ inf. a. macularis sup.+ inf.

(+ media)

Veins corresponding to arteries, often crossing

Arteria cilioretinalis

appearance: 10-33 % Branch from a. ciliaris posterior brevis Enters via discus n.II independently on a. centralis

retinae Acessory arterial supply of macula lutea from

choroid circuit Only source of blood for retina during closure of

a. centralis retinae 90 % temporally - 10 % nasally closure of a. cilioretinalis → central scotoma Closure of a. centralis retinae → spared central

vision of macula lutea

A. cilioretinalis

Venous supply of eye – 3 directions

vv. episcleralesvv. ciliares ant. vv. sclerales sinus venosus

sclerae Schlemmi s. Lauthivv. vorticosae (4 in quadrants of eye ball)v. centralis retinaev. ophthalmica sup. sinus cavernosusv. ophthalmica inf. plexus pterygoideusv. angularis v. facialis v. jugularis int.

! Danger of inflammation spreading !

Nervous supply of eye

n. opticus – sensory– pars intraocularis, canalis, intracranialis

– vagina interna, externa

n. ophthalmicus nn. ciliares longi – sensory n. lacrimalis, n. frontalis, n. nasociliaris – for surrounding nn. ciliares breves ganglion ciliare - autonomous

(sympaticus does not connect, parasympaticus yes)

n.III., n. IV., n.VI – motoric

Nervus opticus

Exvagination of diencephalon (thalamus opticus)

Axons separated by endoneuriumOn the surface are analogs of cerebral

coverings Inside nervus running a. et v. centralis

retinea

OPTICAL PATHProjection → Ascending → Sensory path

4 - neuronal, partially crossed

• neuron: rods and cones of retina• neuron: bipolar cells of retina• neuron: ganglionic cells of retina n. II chiasma

opticum corpus geniculatum laterale• neuron: cells of corpus geniculatum laterale

tractus geniculocorticalis (= radiatio optica Gratioleti) lobus occipitalis, area 17 (around fissura calcarina)

Visual pathsides from 3rd neuron

into hypothalamus (nucleus suprachiasmaticus) – transfers optical signals to highest vegetative centers (sight of food = salivation)

Tracts of pupillary reflex – via area pretectalis to nucleus accessorius dorsalis n. III /Edinger-Westphal/ - parasympatic

path vith n. III ganglion ciliare nn. ciliares breves m. ciliaris et m. sphincter pupillae /miosis + acommodation/

into retikular formation tractus reticulospinalis centrum ciliospinale /Budge/ C8-Th1 sympathetic path in truncus symphaticus ganglion cervicale superius plexus caroticus internus et ophtalmicus nn. ciliares breves m. dilatator pupillae /mydriasis/

Path for convergence nucleus interstitialis /Cajal/ fasciculus longitudinalis medialis nuclei of all eyeball moving nerves

Tectal visual circuit - tractus tectospinalis (direction of eyeball synchro, head and neck towards visual inputs and for coordination of whole body movements)

Acessory apparatus= Structurae oculi pertinentes

Fibrous apparatus = Apparatus ligamentosus

Lids = PalpebraeConjunctiva = ConjunctivaLacrimal apparatus = Apparatus lacrimalisMuscular apparatus = Apparatus musculariseyebrow = Supercilium

Fibrous apparatus

periorbitavagina bulbi (= capsula Tenoni)

– lig. suspensorium bulbi

spatium episcleralecorpus adiposum orbitae fasciae musculares

Conjunctiva = Tunica conjunctiva

t.c.bulbi et palpebrarum fornix superior, inferior Continuation of corneal epithelium, continues from

behind to eyelid, covers ventral side of eyeball Multi layer cylindrical epithelium Contains cup cells Lacrimal film (irroratio lacrimarum) glanduale conjuctivales Wolfringi caruncula lacrimalis

Lids = Palpebrae

palpebra superior, inferior tarsus superior (10 mm), inferior (5 mm) lig. palpebrale med. (2 lines) + lat. facies ant.+post., rima palpebrarum, commissura palp.

med.+lat., limbus ant.+ post. angulus oculi med.+ lat. m. tarsalis sup.(Mülleri) + inf. – smooth muscles pars palpebralis m. orbicularis oculi - n. VII m. levator palpebrae superioris - n. III eyelashes = cilia

Lids = Palpebrae External skin part

– Multi layered flat cuboid epithelium w exfoliation

– gll. sebaceae Zeissi • Ceruminous glands - hordeolum

– eyelashes + gl. ciliares Molli• Apocrine glands

m. orbicularis oculi Tarsal plate

– fibroelastic– gll. tarsales Meibomi

• Ceruminous glands - chalazion

Inner conjunctive part– Epithelial transition - sulcus

Lacrimal apparatus= Apparatus lacrimalis

glandula lacrimalis – pars orbitalis + palpebralis

– 12 – 15 individual ductuli excretorii

glandulae lacrimales accessoriae Krausei rivus lacrimalis lacus, papilla, caruncula lacrimalis puctum, canaliculus lacrimalis saccus lacrimalis ductus nasolacrimalis (plica

lacrimalis Hasneri) meatus nasi inf. In drainage lacrimal pathways more small villi

Glandula lacrimalis tubuloacinous serous glands with myoepitelial

cells

Svalové ústrojí

mm. recti bulbi: sup., inf., med., lat. (VI.)mm. obliqui bulbi: inf., sup.(IV.)

– /fovea trochlearis, spina trochlearis, trochlea, vagina m.o.b.s./

m. levator palpebrae sup. (pars spf.+prof.)n. III – ostatních 5 svalů

hladké svaly: m. orbitalis Mülleri, m. tarsalis sup. Mülleri + inf.

Movements of eyeball I.Movements of eyeball I.

Movements around axes = duction Around vertical axis

– adduction (inside)– abduction (outside)

Around horizontal axis– elevation (sursumduction; supraduction): up– depression (deorsumduction; infraduction): down

Around sagittal axis (ventrodorsal) :– intorsion (incykloduction): flapping inside– extorsion (excykloduction): flapping outside

Movements of eyeball II.Movements of eyeball II.Movements paired (together with both eyeballs)

Same directed conjugated paired movements = version (conjugated movements)– dextroversion (right) + sinistroversion (left)– supraversion (sursumverza) + infra/deorsumverza (up + down)– dextro/sinistroelevation + dextro/sinistrodepression (up/down and to sides)– dextro/sinistrocycloversion (rotation right/left)

Counter directed non conjugated paired movements = vergence (non conjugated movements)– convergence = inside direction of axes from both eyeballs– divergence = outside direction of axes from both eyeballs

strabismus = heterotropie = cross eye:– one eye is persistently rotated inward or outward

Eyeball movements

Strabismus concomitans

esotropie (s. convergens)

exotropie (s. divergens)

hypertropie (s. sursumvergens)

hypotropie (s. deosumvergens)

Development of visual apparatus

neuroectoderm of ventral forebrainSurface ectoderm of head In between mesenchymeCells of neural crest

Development of visual apparatus

Development since 4th weekOrigin of eye rims in ventral forebrainDeepens into eye sacsFormation of eye stalk Induction of ectoderm = thickeningOrigin of eye placode

Development of vision apparatus

Invagination of eye placodeOrigin of hollow lentiform sac w/o

connection with surfaceEye sacs invaginate = eye cup Invagination of stalk and cup with entering

of vascular mesenchyme = origin of vitreal vessels

Development of retina

Origin from eye cupExternal layer – pigment epithelium Inner layer – proliferates in pars nervosa Intraretinal space – gradually disappears

Inversion of retina

Development of nervus opticus

Fibers from ganglionic cells growth through stalk

lumen of stalk ceasesFissure (invagination) ceases

BRAIN

3 brain ‘vesicles’ are subdividing

Cephalic flexure/bend

35 days pcDEVELOPMENT of the EYE I from CNS

Telencephalon

Diencephalon

Mesencephalon

now four, then Rhombencephalon divides into Met- & Mel-encephalons

Cervical flexure

Rhombencephalon

start the folding

Already before 35d pc, on each side of the ‘head’, interactions have started between surface ECTODERM, a bulge of the FOREBRAIN & the MESENCHYME

Surface ECTODERM

MESENCHYME RETINA Neural ECTODERM

CORNEAL EPITHELIUM

EYE PARTS’ EMBRYONIC SOURCES

UVEA

LENS

Connective tissue & muscle (& vessels) come from cranial mesenchyme

Surface ECTODERM

MESENCHYME RETINA Neural ECTODERM

SCLERALENS

CORNEAL STROMA VITREOUS

RETINA

OPTIC NERVE

Two ectoderms drive events and shaping

CORNEAL EPITHELIUM

ANTERIOR EYE PARTS’ EMBRYONIC SOURCES

Surface ECTODERM

LENS

How does a surface layer produce two separate structures?

In much the same way as an endocrine gland is produced: by a downgrowth of cells that then break off the surface connection

Here the downgrowth makes the lens vesicle, conferring a roundish shape from early on

To have enough cells for the future cornea and for the lens vesicle, the surface ectoderm first thickens to form a lens placode

over the brain-derived optic vesicle

Mesenchyme

LENS & OPTIC CUP DEVELOPMENT I

While still growing, both placode and end of the optic vesicle invaginate

lens placode

optic vesicle

Double wall of optic cup is starting to form

Intraretinal space

Mesenchyme

Optic vesicle precedes the lens vesicle and is a distinct structure

OPTIC CUP DEVELOPMENT II: Choroid fissure

Together with the invagination centrally at the end of the optic cup,

MesenchymeBlood vessels have to be introduced early into the soon to be enclosed round eye

an invagination along the cup & stalk’s inferior surface occurs, to create the choroid fissure

in which runs the hyaloid artery

OPTIC CUP DEVELOPMENT II: Coloboma

Together with the invagination centrally at the end of the optic cup,

Blood vessels have to be introduced early into the soon to be enclosed round eye

an invagination along the cup & stalk’s inferior surface occurs, to create the choroid fissure

in which runs the hyaloid arteryAlso, an annular vessel

runs around the outside of the optic cup

Mesenchyme

Imagine a penis in which the urethra near & into the glans is still open on its underside - the condition of hypospadias - (but now contains an artery)

Defects in the eye from failure of the choroid fissure to close are colobomas

MesenchymeMesenchyme

OPTIC DEVELOPMENT III: Lens vesicle

Deeper part of Placode sinks into mesenchyme & makes a vesicle

Attachment to surface ectoderm will be broken

LENS VESICLE

Optic cup becomes deeper

Inner wall thickenslens placode

so that surface ectoderm can become corneal epithelium & intervening mesenchyme can form the corneal stroma

OPTIC DEVELOPMENT IV: Lens differentiation

Posterior vesicle cells become elongated lens cells

Attachment to surface ectoderm lostMesenchyme

Anterior vesicle cells become subcapsular epithelium

Mesenchyme

Basal lamina becomes lens capsule

Posterior vesicle cells form the nucleus of the lens. Subsequent lens cells derive from the subcapsular epithelium

OPTIC DEVELOPMENT IV: Lens differentiation

Posterior-vesicle cells elongate to lens cells

Anterior-vesicle cells become subcapsular epithelium

Mesenchyme

Basal lamina becomes lens capsule

Lumen obliterated

LENS

OPTIC DEVELOPMENT V: Retina differentiation I

Outer layer of cup stays thin and beomes pigment cell layer

Intra-retinal space occluded

Mesenchyme

Inner layer of cup thickens and becomes Neural layer

Hyaloid artery reaches inside cup

After a while, the lens and vitreous no longer need it, and it atrophies. Only the neural retina continues to depend on it, but under another name - central artery of the retina

OPTIC DEVELOPMENT VI: Retina differentiation II

MesenchymeInner layer of cup thickens and becomes Neural layer

Where cells multiply, form layers and differentiate to the several cell types of the neural retina

Outer layer of cup stays thin and beomes pigment cell layer

Development of ciliary body

Protrusion of both layers of eye cuppigment epithelium – from external layerNon pigmented epithelium – from inner

layerCilliary canal – from cavity of cupm. ciliaris and tissue – from mesenchyme

Iris development

Margin of eye cupExternal layer changes into smooth muscles Inner layer creates pigment epithelium

Lens development Originates from lentiform sac

– Anterior wall is not changing = anterior epithelium

– Posterior wall – cells elongating till lumen extinction

• Origin of primary fibers• Secondary fibers – from cells of

anterior epithelium

– capsula lentis – thickened basal lamina of anterior epithelium

Supplied by a. hyaloidea – ceases Pupillary membrane – covers lens

– ceases

Development of eye chambers

Anterior chamber – Rift between origin of lens and cornea

Posterior chamber– Rift inside eye cup alongside lens

Development of cornea, uvea and sclera

cornea– Surface mesoderm– mesenchyme– Cells of neural crest

Choroidea and sclera – Surrounding mesenchyme

Development of eye palpebras

6th week: skin folds over cornea 10th week: folds connectiong 28th week: again opening During that time from inside attaches conjunctiva

Muscle from IInd branchial arch Tarsal plate and glands from mesenchyme

Development of lacrimal glands

Invagination of surface ectoderm

Non functional till approx. 6th week after delivery– Newborn is not lacrimating

Developmental defects Inborn retinal dystopia coloboma retinae (usually bilateral – defect of fissura optica

closure) cyclopia (1 eye), synophthalmia (fused eyes) microphthalmia – infection anophthalmia coloboma iridis (6th week – defect of fissura optica closure aniridia, aphakia membrana pupillaris persistens a. hyloidea persistens Inborn green cataracta; inborn cataracta (in galactosemia) Inborn ptosis, coloboma palpebrale cryptophthalmia (eyelids missing – eye covered by skin)

Examination

Slit-lampExamination of the eye ground – oedema of

discus/papilla n. optici = increased intracranial pressure

perimetria = examination of the width of the eye field

optometria = examination of the quality of vision

OCT (optical coherence tomography)

Goldmann applanation tonometry

OCT

Slit lampOCT

Symptomes and malfunctions epiphora (excesive lacrimation) myopia – hypermetropie (short – long vision) hypermetria (overshooting – lesion of cerebellum!) presbyopia (elder eye) hemeralopia (anopsia in twilight) amblyopia (blunt-sighted) – functional lesion (ce when

strabismus) daltonismus (colorless vision)