Radionuclide Generators

Radionuclide Generators Downloaded from pubs.acs.org by 95.181.177.95 on 12/02/18. For personal use only.

A u t h o r Index Anderson, Wendie, 215 A t c h e r , R o b e r t W., 215 B a r k e r , S. L., 135 B a r n e s , J . W., 123,179 B e n t l e y , G l e n n E., 169,179 B e r g n e r , Β., 135 B e t t , R., 35 Brihaye, C , 185 B u d i n g e r , T. F., 97,199 B u t l e r , Τ. Α., 51 Cahoon, J . L., 97 Cuninghame, J . G., 35 deJong, R o l f , 23 Dymond, D. S., 35 E l l i o t t , A. T., 35 F l a t m a n , W., 35 Friedman, A r n o l d Μ., 215 Gansow, O t t o A., 215 Gennaro, G. P., 135 G u i l l a u m e , M., 185 Haney, Τ. Α., 135 Huesman, R. Η., 97 Johnson, P. C., 151 Knapp, F. F., J r . , 51 K r o h n , Κ. Α., 199 Lamb, J . F., 67 L e B l a n o , Α., 151 Lindeyer, J . , 3 Link, Daniel C , 215 L o b e r g , M. D., 135 Ma, J . M., 67 Marcus, C a r o l , 23

Mausner, Leonard F., 77 Mena, I s m a e l , 23 Moyer, B. R., 199 M u l l e r , W. R., 135 N e i r i n c k x , R. D., 135,151 O ' B r i e n , G. Μ., 51 O ' B r i e n , Η. Α., J r . , 179 O t t , Μ. Α., 179 P a c k a r d , A. B., 51 Panek, K. J . , 3 P h i l p , M. S., 67 P r a c h , Thomas, 77 Ramsey, C. I . , 67 R i c h a r d s , P o w e l l , 77 S c h e i n b e r g , D a v i d Α., 215 S e e v e r s , Robert Η., 215 S e u r e r , F. Η., 179 Sims, Η. Ε., 35 S t e i n k r u g e r , F r e d J . , 169,179 S t o n e , D. L., 35 S t r a n d , M e t t e , 215 T a y l o r , W. Α., 179 Thomas, Κ. E., 123 T r e v e s , S., 51 Trumper, J . , 151 van d e r V l u g t , H. C., 3 Wanek, P h i l Μ., 169 W a r a n i s , Α., 135 W i l l i s , Η. H., 35 W o l f , W a l t e r , 23 Yano, Υ., 97,199 Y a r n a i s , Α., 135

Subject Index A s t a t i n e - 2 1 1 , h a l f - l i f e , 216 Au-191, s o r b e n t / c o m p l e x c o m b i n a t i o n , 9 Au-195, a c t i v i t y , 44 A c t i v i t y , i n t e g r a t e d , e q u a t i o n , 144 Au-195 m Adsorbents a d v a n t a g e s , 24 e v a l u a t i o n , 154 e l u a t e decay, 2 9 f Ta-178 g e n e r a t o r , 151-68 e l u t i o n e f f i c i e n c y , 38 A d s o r p t i o n - e l u t i o n problem, 5 e l u t i o n y i e l d , 17f Ag-109m v s . f l o w r a t e , 191Γ decay, 179 v s . mercury a c t i v i t y , 17f h a l f - l i f e , 179 f o r m a t i o n r a t e , 187t Ag-109m g e n e r a t o r , 182f gamma e m i s s i o n s , 2 8 t Alumina, hydrated, 5 h a l f - l i f e , 31,187t A l z h e i m e r s t y p e d e m e n t i a , 99 s t e r i l i t y and p y r o g e n i c i t y , 25-26 Ammonium c h l o r i d e , Sr-82 i s o l a t i o n , 129 Au-195m e l u t i o n Antibodies column p e r f o r m a n c e , 38 l i n k i n g t o m e t a l , 225 cyanide e f f e c t s , 39f,40f m o d i f i c a t i o n o f m e t a l c h e l a t e s , 218 e f f i c i e n c y , 38 r a d i o i o d i n a t e d , 215 A

1

231

r a d i o n u c l i d e

232 Au-195m g e n e r a t o r a b s o l u t e y i e l d , 32 u s e , 31 u s e f u l n e s s , p e r f o r m a n c e , 23-34 Au-195m r a d i o i s o t o p e , p r o d u c t i o n , 3-21 Au-198, a d s o r p t i o n , 8-10 Au-198 c o m p l e x e s , e l u t i o n y i e l d , 10t Β B L I P — S e e LINAC i s o t o p e producer Ba-128, h a l f - l i f e , 98t Batch a d s o r p t i o n , 7 Bi-212 c h e l a t i o n t o monoclonala n t i b o d y , 215-27 r a d i o n u c l i d i c g e n e r a t o r , 216 use i n r a d i o t h e r a p y , 215-27 B i f u n c t i o n a l m e t a l c h e l a t e s , 221f B i g m o l y s , 125 B l o o d p o o l s , d e t e r m i n a t i o n , 90 B o l u s e l u t i o n , 186 e x p e r i m e n t a l c o n d i t i o n s , 190 B o l u s i n f u s i o n s t u d i e s , 112f B o l u s i n j e c t i o n , 196 B o l u s peak, 187 B r a i n b l o o d f l o w , s t u d y i n g , 97 B r a i n s t u d i e s , Rb-82, 118 B r a i n t u m o r s , 99 F - 1 3 - f l u o r o d e o x y g l u c o s e PET, 120f Rb-82 s t u d i e s , 120f Breakthrough, 192 B r o m i n e , d e p o s i t i o n , Ag e l e c t r o d e , 174 C 1-(£-Carboxymethoxybenzyl)EDTA, i r o n c o m p l e x , 222 C a r d i o g r a p h y , Kr-81m r e q u i r e d a c t i v i t y v a l u e s , 194t C a r d i o l o g y , d i a g n o s t i c g e n e r a t o r , 19 C a r r i e r added m e t a l s o l u t i o n s , 225 C a t e c h o l , O s - 1 9 1 / I r - 1 9 1 m g e n e r a t o r , 60 C a t i o n - c r y p t a n d c o m p l e x e s , 201 C a t i o n exchange r e s i n , r a d i o a c t i v i t y e f f e c t , 68 Cd-109 h a l f - l i f e , 179 i m p u r i t i e s from p r o t o n bom­ bardment, 180t i r r a d i a t i o n , 180 p r o d u c t i o n , 182f p a r a m e t e r s , 183t s e p a r a t i o n from i m p u r i t i e s , 180 Cd-109/Ag-109m e l e c t r o l y t i c g e n e r a t o r s y s t e m , 172 use i n USLR g e n e r a t o r s , 4t C e r e b r a l p e r f u s i o n , 67 C l i n i c a l use, o p t i m a l con­ d i t i o n s , 185,192-96

g e n e r a t o r s

C o n t i n u o u s e l u t i o n method, 186 C o n t r o l pore g l a s s l i p o a m i d e s , 37 e l u t i o n e f f i c i e n c y , 42f C o r o n a r y b y p a s s , Rb-82 g e n e r a t o r , 117f Cow s y s t e m , 187 Crown e t h e r s , 200 C r y p t a n d [2.2.2] complex, 202f C r y p t a n d s , 200 C r y p t a t e complexes g e n e r a t o r produced i s o t o p e s , 199-214 s y n t h e s i s , 201 Cryptâtes, 200 d i s s o c i a t i o n c o n s t a n t s , 202f Cu-62, 174 Cu-67, p r o d u c t i o n , 173 Cyclam, 200 C y c l i c p o l y e t h e r s , as p h a r m a c o k i n e t i c m o d i f i e r s , 200 D Daughter a c t i v i t y , f o r m a t i o n r a t e , 187 D i a g n o s t i c i m a g i n g , 215 t r a n s - D i o x o t e t r a c y a n o o s m a t e ( V I ) , 61 t r a n s - D i o x o t e t r a h y d r o x o o s m a t e ( V I ) , 61 D i s t r i b u t i o n c o e f f i c i e n t , equation, 7 D i t h i o c e l l u l o s e , d i s a d v a n t a g e , 37 Ε Electrochemistry, radiochemical g e n e r a t o r systems, 169-75 E l e c t r o l y t i c g e n e r a t o r s y s t e m , 172 Electrolytic separation, f e a s i b i l i t y e v a l u a t i o n , 173 E l u e n t , sodium t h i o s u l f a t e , 14 Elution b o l u s method, 186 c o n t i n u o u s method, 186 o f daughter n u c l i d e , 186-92 e q u i l i b r i u m l e v e l , 187 gamma i r r a d i a t i o n e f f e c t , 44t Elution yield d e f i n i t i o n , 189 measurement, 189-92 E n z a c r y l p o l y t h i o l , 37 F Fe-52 h a l f - l i f e , 98t,180 i m p u r i t i e s , p r o t o n bombardment, 181t i r r a d i a t i o n , 181 p r o d u c t i o n , 80,182f parameters, 82t,183t s e p a r a t i o n from i m p u r i t i e s , 181 v a l e n c e s t a t e c o n t r o l , 181 Fe-52/Mn-52m g e n e r a t o r , 78-85 See a l s o Radiomanganese s t u d i e s a n i m a l s t u d i e s , 84,86

INDEX

233

Fe-52/Mn-52m g e n e r a t o r — C o n t i n u e d decay c h a r a c t e r i s t i c s , 7 9 f e l u t i o n p r o f i l e , 82f F i r s t pass a n g i o g r a p h y , 35 generator p a i r requirements, 36t Hg-195m/Au-195m g e n e r a t o r , 35-50 o p e r a t i n g requirements, 37t F o r m a t i o n r a t e , daughter a c t i v i t y , 187

G a l l i u m - 6 8 , 222 Gamma i r r a d i a t i o n , e f f e c t on e l u t i o n e f f i c i e n c y , 44t Ge-68, h a l f - l i f e , 98t G e n e r a t o r column, c r o s s s e c t i o n , 13f G e n e r a t o r d e s i g n , m e c h a n i c s , 47 G e n e r a t o r p a i r , d e f i n i t i o n , 36 Generator r a d i o n u c l i d e s , l a b e l i n g cryptâtes, 2 1 2 t G e n e r a t o r s t e r i l i z a t i o n , 16 G e n e r a t o r s y s t e m , r e q u i r e m e n t s , 169-70 Gold See a l s o Au-198 adsorption, 8 e l u t i o n y i e l d , 10t sorbent/complex c o m b i n a t i o n s , 9 Gold-195m See a l s o Au-195m p r o d u c t i o n , 3-21 H HMDO—See Manganese d i o x i d e , h y d r a t e d Heart s t u d i e s , p o s i t r o n e m i s s i o n tomography, 115,118 Hg-195, v a r i a t i o n o f a c t i v i t y , 4 3 f Hg-195m a c t i v i t y , 44 b r e a k t h r o u g h , 25,28f i n Au-195m g e n e r a t o r , 3 0 f v a r i a t i o n w i t h t i m e , 45t column a d s o r p t i o n , 37 column l o a d i n g , 12 decay, 2 7 f scheme, 4 6 f gamma e m i s s i o n s , 2 8 t p r o d u c t i o n , 11,23,36 v a r i a t i o n o f a c t i v i t y , 43f Hg-195m/Au-195m g e n e r a t o r , 1 8 f , 2 7 f , 4 8 f performance, 12 p r e p a r a t i o n , c h a r a c t e r i s t i c s , 35-50 use i n USLR g e n e r a t o r s , 4 t Hg-203 a d s o r p t i o n , n i t r a t e s y s t e m , 7,8t I 1-122, r a p i d i o d i n a t i o n s , 90 1-122 g e n e r a t o r , scheme, 8 9 f Indium-111, 222

I n t e g r a t e d a c t i v i t y , e q u a t i o n , 144 I o d i n a t i o n , 1-122, 90 Ir-191m, r a d i o n u c l i d e angiogram, 6 4 f Κ K i d n e y , cryptâtes, 203 K r - 8 l m , 67 f o r m a t i o n r a t e , 187t h a l f - l i f e , 187t r e q u i r e d a c t i v i t y v a l u e s , 194t Kr-8lm g e n e r a t o r , 67-68 a c t i v i t i e s , 195f lung p e r f u s i o n scan, 72f t i m e - a c t i v i t y p r o f i l e , I88f L L a b e l i n g cryptâtes, r a d i o n u c l i d e s , 212t Leukemic m i c e , In—111 DTPA, 2 2 3 f LINAC i s o t o p e p r o d u c e r , r a d i o n u c l i d e p r o d u c t i o n , 77-96 Lung p e r f u s i o n s c a n , Kr-81m, 7 2 f M Manganese d i o x i d e as a d s o r b e n t , 167 hydrated, 5 Mercury See a l s o Hg-195m a d s o r p t i o n , 7-8 a d s o r p t i o n , i n n i t r a t e s y s t e m , 7,8t b i n d i n g , 37 t h i o l b i n d i n g , 45 M e t a l , l i n k i n g t o a n t i b o d y , 225 Metal c h e l a t e s a n t i b o d y m o d i f i c a t i o n , 218 b i f u n c t i o n a l , 221f M e t a l s o l u t i o n s , c a r r i e r added, r e a c t i o n s , 225 M i c e , i n j e c t e d w i t h In-111 DTPA, 223f M i l k i n g p r o c e d u r e , 88 Mn-52m gamma s p e c t r u m , 8 3 f Mn-52m g e n e r a t o r , 182f Mn-54 c h l o r i d e , b l o o d c l e a r a n c e , 8 5 f Molybdenum m e t a l t a r g e t , arrangement and p a c k a g i n g , 126f M o n o c l o n a l a n t i b o d i e s , imaging and t h e r a p y , 225 M y o c a r d i a l b l o o d f l o w , Rb-82, 119f M y o c a r d i a l i n f a r c t i o n , Rb-82, 115 M y o c a r d i a l i s c h e m i a , 115 M y o c a r d i a l p e r f u s i o n , 67 Fe-52/Mn-52m g e n e r a t o r , 78 s t u d i e s , Rb-82 g e n e r a t o r , 1 l 6 f Myocardium-to-blood r a t i o a n i m a l s t u d i e s , 84 radiomanganese s t u d i e s , 78

RADIONUCLIDE

234

GENERATORS

0

R a d i o l a b e l e d monoclonal a n t i b o d i e s , 225 Radiomanganese s t u d i e s , myocardiumt o - b l o o d c o n c e n t r a t i o n , 78 Organic r e s i n s , r a d i o l y t i c R a d i o n u c l i d e angiogram d e g r a d a t i o n , 136 Ir-191m, 64f Os-191 p e d i a t r i c , 63-65 m a x i m i z i n g y i e l d , 52-53 Radionuclide generator y i e l d , p r o d u c t i o n , 52 d e t e r m i n a t i o n by t u b e method, 191f c o n t a m i n a n t s , 54 R a d i o n u c l i d i c p u r i t y , m a i n t a i n i n g , 45 scheme, 52 R a d i o p h a r m a c e u t i c a l s , b i o d i s t r i b u t i o n , 211 r a d i o n u c l i d e s p r o d u c e d , 53t R a d i o t h e r a p y , B i - 2 1 2 , 215-27 Os-191/Ir-191m g e n e r a t o r Rauscher e r y t h r o l e u k e m i a , 225 a d v a n t a g e s , 51 Rb a c t i v i t y , d i s t r i b u t i o n p r o f i l e a n i o n exchange r e s i n , 56t a s s e m b l y , 54-56 on a column, 193f b r e a k t h r o u g h , column e f f e c t , 58t Rb-81, p r o d u c t i o n , 67 e l u e n t , HCl e f f e c t s , 59 Rb-81/Kr-81m p e r f u s i o n g e n e r a t o r , 67-76 e l u e n t s , 60t Rb-81 b r e a k t h r o u g h , 69 HCl e f f e c t , 57t Rb-81 w a s h o f f , 7 0 f , 7 1 f l i g a n d e f f e c t s , 58t Rb-82 b r e a k t h r o u g h , 143 m a l o n i c a c i d v s . c h l o r o g e n e r a t o r , 63 d a u g h t e r , r e g e n e r a t i o n , 136 new d e s i g n s , 61-62 e l u t i o n p r o f i l e , 144,145f performance, 51-66 f o r m a t i o n r a t e , 187t s a l i n e wash, a d d i t i o n s , 60t scavenger column, 57-59 h a l f - l i f e , 187t use i n USLR g e n e r a t o r s , 4t p h a r m a c e u t i c a l q u a l i t y , 135-50 Osmium—See Os-191, 52-54 Rb-82 g e n e r a t o r , 101t Osmium m e t a l , o x i d a t i o n , 55 a l u m i n a column e f f e c t s , 102,103f Oxides s i l i c a g e l , h y d r a t e d , 5 automated, 106f m i c r o p r o c e s s o r c o n t r o l l e d , 97-122 Ρ b r e a k t h r o u g h c h a r a c t e r i s t i c s , 109 c h e c k i n g the r a d i o a c t i v e d o s e , 109 Parent i s o t o p e a d s o r p t i o n , 5 c o n s t r u c t i o n , 104,108 Pb-212 c o r o n a r y b y p a s s , 117f immune r e s p o n s e r e d u c t i o n , 220f development, 99 r a d i o n u c l i d i c g e n e r a t o r , 216 e l u t i o n , 109 y i e l d , 219f e l u t i o n t i m e t o d e l i v e r , 112f Pediatric radionuclide e l u t i o n y i e l d , 11 Of a n g i o g r a p h y , 63-65 s t e a d y - s t a t e c o n d i t i o n s , 111f Perfusion generator, c l i n i c a l i n f u s i o n system, 136,140,141f,142f m i c r o p r o c e s s o r c o n t r o l l e r , 107f u s e , 192-96 myocardial perfusion studies, 1l6f P E T — S e e P o s i t r o n e m i s s i o n tomography Phosphates, 5 NaCl e f f e c t s , 103f Pneumology, Kr-81m, r e q u i r e d a c t i v i t y o p e r a t i o n , 104,108 v a l u e s , 194t r a d i o n u c l i d e s i n e l u e n t s , 114t Polarographic apparatus, e l e c t r o ­ Sr-82 l o a d i n g , 105f c h e m i c a l c e l l , 170,171f Sr-82/85 l o a d i n g , 104 P o l a r o g r a p h i c h a l f wave p o t e n t i a l s , 172t s t e a d y - s t a t e a c t i v i t y , 147f P o s i t r o n e m i s s i o n tomography, 97-122 t o t a l a c t i v i t y , 146f h e a r t s t u d i e s , 115,118 Rb-82m, d e c a y , 67 P o s i t r o n e m i t t e r s , g e n e r a t o r s , 98t Rb-82/Sr-82 g e n e r a t o r P r o d u c t i o n and r e c o v e r y , m e d i c i n e r a d i a t i o n d o s i m e t r y , 115 Sr-82 l o a d i n g s , 113t systems, 179-84 Recovery, f o r n u c l e a r m e d i c i n e P r o t e i n l o c a l i z a t i o n , 215 g e n e r a t o r systems, 179-84 R u b i d i u m - 8 2 — S e e Rb-82 g e n e r a t o r R Ra-224 g e n e r a t o r , d i a g r a m , 221f R a d i a t i o n d o s i m e t r y , Rb-82/Sr-82, 115 R a d i o c h e m i c a l p u r i t y , b r e a k t h r o u g h , 192 R a d i o i o d i n a t e d a n t i b o d i e s , 215 R a d i o i s o t o p e , s e l e c t i o n , 179

S Sb-121/Te-118 r e a c t i o n , e x c i t a t i o n , Sepharose columns, e l u t i o n e f f i c i e n c y , 41f

93f

INDEX

235

S h o r t - l i v e d daughter n u c l i d e e l u t i o n , 186-92 S h o r t - l i v e d r a d i o n u c l i d e generator o p t i m a l c l i n i c a l use, 185-99 p h y s i c a l c h a r a c t e r i s t i c s , 185-99 Short-lived radionuclides, advantages, 78 S i l i c o n d i o x i d e - Z n S s o r b e n t , 15 S i l i c o n dioxide-ZnS/Au-198, elution y i e l d v s . m o l a r i t y , 13f Silver cryptate b l o o d c l e a r a n c e , 206f d i s s o c i a t i o n , 203 organ d i s t r i b u t i o n , 205f t i s s u e d i s t r i b u t i o n , 204f S i l v e r c r y p t a t e complex, b l o o d c l e a r a n c e c u r v e , 203 Sodium c y a n i d e , 38 Sodium t e t r a c h l o r o a u r a t e , 8 Sodium t h i o s u l f a t e as e l u e n t , 14 r a d i a t i o n d e c o m p o s i t i o n , 14 Sodium t h i o s u l f a t e / s o d i u m n i t r a t e , e l u e n t s p e c i f i c a t i o n s , 19t Sodium t h i o s u l f a t o a u r a t e , 15 Sorbents, 5 Sr-82 b r e a k t h r o u g h , 148f,149 f i n a l p r o d u c t c h a r a c t e r i s t i c s , 132t h a l f - l i f e , 98t l a r g e - s c a l e i s o l a t i o n , 123-34 l o a d i n g , 104,113t p r o d u c t i o n , 99,102,129t S r - 8 2 i s o l a t i o n , 123 ammonium c h l o r i d e wash, 129 d i s s o l u t i o n , 129 f l o w scheme, 124f,127f ion exchange, 128 t i m e r e q u i r e m e n t , 130t y t t r i u m e l u t i o n , 130 Sr-82/Rb-82 decay scheme, 100f S r - 8 5 , h a l f - l i f e , 102 S t e r i l i z a t i o n , 15-16 Strontium cryptate b l o o d c l e a r a n c e , 21 Of b l o o d - f l o w r a d i o p h a r m a c e u t i c a l s , 208 t i s s u e d i s t r i b u t i o n , 209f Strontium(IT), distribution c o e f f i c i e n t i n N a C l , 139f Τ Ta-178 a c i d i c e l u e n t s , 167 adsorption r a t e , I63f autoclaving e f f e c t , I64,l65t d i s s o l u t i o n , 155 distribution c o e f f i c i e n t s , 159f,161f,I63f e f f e c t o f e l u e n t a d d i t i v e s , 166t

Ta-178—Continued h a l f - l i f e , 152 partition c o e f f i c i e n t s , 153-54,156-58t r a d i o n u c l i d e p r o p e r t i e s , 152 tungsten breakthrough, 164,l66t Ta-178 g e n e r a t o r a d s o r b e n t s , 151-68 o r g a n i c breakdown p r o d u c t , 167 trimethylamine concentration i n eluent, I66t Tc-99m, 222 formation r a t e , I87t h a l f - l i f e , I87t Te-118 d e c a y , 91 h a l f - l i f e , 98t Te-118/Sb-118 decay c h a r a c t e r i s t i c , 92f Te-118/Sb-118 g e n e r a t o r s , 91-94 Th-228, d e c a y , 2 l 6 , 2 1 7 f Th-228 g e n e r a t o r , 217f T H I O — S e e Sodium t h i o s u l f a t e T h i o l , mercury b i n d i n g , 45 T h i o p r o p y l sepharose-6B, 37 T h o r i u m - c o n t a i n i n g t i t a n a t e column, 218 T i t a n a t e columns, w i t h t h o r i u m , 218 Tomography, p o s i t r o n e m i s s i o n , 97-122 Tube method, 191Γ Tumor i m a g i n g , 225 Tumor t h e r a p y , 215 Tungsten See a l s o W-178 adsorption r a t e , I63f distribution c o e f f i c i e n t , 159f,161f,I63f p a r t i t i o n c o e f f i c i e n t , 153-54,156-58t

U USLR—See U l t r a s h o r t - l i v e d radionuclides Ultra short-lived radionuclides, 3 a d s o r p t i o n - e l u t i o n problem, 5 b a t c h a d s o r p t i o n e x p e r i m e n t s , 7-11 economics, 4 g e n e r a t o r s , 4t c a n d i d a t e s , 4t i s o t o p e s p e c i f i c a t i o n , 4t Os-191/IR-191m g e n e r a t o r , 51-66 s e p a r a t i o n system, 6 t

V Venography, 67 Kr-81m, r e q u i r e d a c t i v i t y , 194t V i c i n a l d i t h i o c e l l u l o s e , disadvantage as e l u e n t , 37

RADIONUCLIDE

236

w W-178 a d s o r p t i o n r a t e , I63f distribution coefficients, 159f,161f,163f p a r t i t i o n c o e f f i c i e n t , 153-54,156-58t Water r a d i o l y s i s , p r o d u c t s , 44t X Xe-122 half-life,

98t

Xe-122—Continued p r o d u c t i o n , 86 Xe-122/1-122 g e n e r a t o r , 86-90 decay c h a r a c t e r i s t i c s , m i l k i n g p r o c e d u r e , 88

GENERATORS

87f

Ζ Zirconium oxide, hydrated, Zn-62, h a l f - l i f e , 98t

5